03039nas a2200385   4500008004100000022001400041245012200055210006900177260001600246300000700262490000700269520175100276653001502027653001102042653001302053653004202066653001102108653002302119653001802142100002802160700002302188700002602211700002402237700002602261700003202287700003302319700002802352700003002380700001802410700002102428700002002449700001902469700002502488856014002513       2025                        eng d  a1479-587600aA genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.0 agenomic strategy for precision medicine in rare diseases integra  c2025 Jan 20  a860 v233 a<p><b>BACKGROUND: </b>Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.</p><p><b>METHODS: </b>Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.</p><p><b>RESULTS: </b>Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.</p><p><b>CONCLUSION: </b>This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.</p>10aAlgorithms10aFemale10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aPrecision Medicine10arare diseases1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aPerez-Florido, Javier1 aMarcos-Luque, Irene1 aFernández, Raquel, M1 aFernandez-Rueda, Jose, Luis1 adel Pozo, María, González-1 aMartín-Sánchez, Marta1 aFernández-Suárez, Elena1 aMena, Marcela1 aCarmona, Rosario1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/genomic-strategy-precision-medicine-rare-diseases-integrating-customized-algorithms-clinical-practice03981nas a2200661   4500008004100000022001400041245015900055210006900214260001600283300000900299490000700308520173000315653001002045653000902055653001602064653001302080653002502093653001002118653001102128653003202139653003002171653002102201653000902222653001102231653001802242653000902260653001602269653001702285653001802302100004002320700002902360700003102389700003302420700002002453700002602473700002902499700003502528700003002563700003402593700003002627700002502657700003602682700003002718700003402748700002802782700002802810700002902838700003002867700002902897700003602926700003102962700003502993700003203028700003303060700001903093700002603112856018103138       2025                        eng d  a2045-232200aMetatranscriptomic analysis reveals gut microbiome bacterial genes in pyruvate and amino acid metabolism associated with hyperuricemia and gout in humans.0 aMetatranscriptomic analysis reveals gut microbiome bacterial gen  c2025 Mar 22  a99810 v153 a<p>Several pathologies with metabolic origin, such as hyperuricemia and gout, have been associated with the gut microbiota taxonomic profile. However, there is no evidence of which bacterial genes are being expressed in the gut microbiome, and of their potential effects on hyperuricemia and gout. We sequenced the RNA of 26 fecal samples from 10 healthy normouricemic controls, 10 with asymptomatic hyperuricemia (AH), and six gout patients. The coding sequences were mapped to KEGG orthologues (KO). We compared the expression levels using generalized linear models and validated the expression of four KO in a larger sample by qRT-PCR. A distinct genetic expression pattern was identified among groups. AH individuals and gout patients showed an over-expression of KOs mainly related to pyruvate metabolism (Log2foldchange > 23, p-adj ≤ 3.56 × 10), the pentose pathway (Log2foldchange > 24, p-adj < 1.10 × 10) and purine metabolism (Log2foldchange > 22, p-adj < 1.25 × 10). AH subjects had lower expression of KO related to glycine metabolism (Log2foldchange=-18, p-adj < 1.72 × 10) than controls. Gout patients had lower expression (Log2foldchange=-22.42, p-adj < 3.31 × 10) of a KO involved in phenylalanine biosynthesis, in comparison to controls and AH subjects. The over-expression seen for the KO related to pyruvate metabolism and the pentose pathway in gout patients´ microbiome was validated. There is a differential gene expression pattern in the gut microbiome of normouricemic individuals, AH subjects and gout patients. These differences are mainly located in metabolic pathways involved in acetate precursors and bioavailability of amino acids.</p>10aAdult10aAged10aAmino Acids10aBacteria10aCase-Control Studies10aFeces10aFemale10aGastrointestinal Microbiome10aGene Expression Profiling10aGenes, Bacterial10aGout10aHumans10aHyperuricemia10aMale10aMiddle Aged10aPyruvic Acid10aTranscriptome1 aMartínez-Nava, Gabriela, Angélica1 aAltamirano-Molina, Efren1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aLozada-Pérez, Carlos1 aHerrera-López, Brígida1 aMartínez-Gómez, Laura, Edith1 aMartínez-Armenta, Carlos1 aGuido-Gómora, Dafne, Lissete1 aValle-Gutiérrez, Sarahí1 aSuarez-Ahedo, Carlos1 aCamacho-Rea, María, Del Carmen1 aMartínez-García, Mireya1 aGutiérrez-Esparza, Guadalupe1 aAmezcua-Guerra, Luis, M1 aZamudio-Cuevas, Yessica1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Yaneth, Citlalli1 aLagunas-Martínez, Alfredo1 aMéndez-Salazar, Eder, Orlando1 aFrancisco-Balderas, Adriana1 aPalacios-González, Berenice1 aPineda, Carlos1 aLópez-Reyes, Alberto  uhttp://clinbioinfosspa.es/content/metatranscriptomic-analysis-reveals-gut-microbiome-bacterial-genes-pyruvate-and-amino-acid-metabolism-associated-hyperuricemia-and-gout-humans02821nas a2200517   4500008004100000022001400041245009100055210006900146260001600215490000700231520126600238653001901504653001001523653001101533653001901544653002201563653002501585653001801610653001101628653000901639653003601648653001001684653002801694100002001722700002201742700002801764700002901792700002001821700002001841700002801861700002301889700002001912700002101932700002101953700002601974700002102000700002602021700002402047700001902071700002002090700001702110700002502127700001902152700002502171856010702196       2024                        eng d  a2073-442500aCharacterization of the Common Genetic Variation in the Spanish Population of Navarre.0 aCharacterization of the Common Genetic Variation in the Spanish   c2024 May 040 v153 a<p>Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35% classified as common (MAF > 1%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF ≤ 1%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.</p>10aCohort Studies10aExome10aFemale10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aHumans10aMale10aPolymorphism, Single Nucleotide10aSpain10aWhole Genome Sequencing1 aMaillo, Alberto1 aHuergo, Estefania1 aApellániz-Ruiz, María1 aUrrutia-Lafuente, Edurne1 aMiranda, María1 aSalgado, Josefa1 aPasalodos-Sanchez, Sara1 aDelgado-Mora, Luna1 aTeijido, Óscar1 aGoicoechea, Ibai1 aCarmona, Rosario1 aPerez-Florido, Javier1 aAquino, Virginia1 aLópez-López, Daniel1 aPeña-Chilet, Maria1 aBeltran, Sergi1 aDopazo, Joaquin1 aLasa, Iñigo1 aBeloqui, Juan, José1 aAlonso, Ángel1 aGomez-Cabrero, David  uhttp://clinbioinfosspa.es/content/characterization-common-genetic-variation-spanish-population-navarre01423nas a2200205   4500008004100000022001400041245007300055210006900128260001300197300001400210490000700224520074300231100002700974700003001001700002301031700002401054700002001078700002001098856009901118       2024                        eng d  a2001-037000adrexml: A command line tool and Python package for drug repurposing.0 adrexml A command line tool and Python package for drug repurposi  c2024 Dec  a1129-11430 v233 a<p>We introduce drexml, a command line tool and Python package for rational data-driven drug repurposing. The package employs machine learning and mechanistic signal transduction modeling to identify drug targets capable of regulating a particular disease. In addition, it employs explainability tools to contextualize potential drug targets within the functional landscape of the disease. The methodology is validated in Fanconi Anemia and Familial Melanoma, two distinct rare diseases where there is a pressing need for solutions. In the Fanconi Anemia case, the model successfully predicts previously validated repurposed drugs, while in the Familial Melanoma case, it identifies a promising set of drugs for further investigation.</p>1 aEsteban-Medina, Marina1 aRoque, Víctor, Manuel de1 aHerráiz-Gil, Sara1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aLoucera, Carlos  uhttp://clinbioinfosspa.es/content/drexml-command-line-tool-and-python-package-drug-repurposing04620nas a2201141   4500008004100000022001400041245011000055210006900165260000900234300001200243490000700255520126600262653002401528653001301552653002301565653001101588653001501599653002001614100001901634700002301653700002201676700002101698700002001719700002301739700002101762700002601783700001901809700002001828700001901848700002201867700002301889700002401912700001701936700002101953700001701974700001601991700002402007700002502031700002502056700002302081700002302104700002702127700002402154700001602178700002102194700002602215700002502241700002102266700002102287700001902308700003202327700002102359700002202380700002002402700001902422700002602441700001802467700001802485700002302503700002102526700001902547700001902566700002202585700001802607700001902625700001802644700002302662700001802685700002002703700001902723700003302742700002602775700002702801700002502828700002302853700001802876700002302894700001702917700002402934700001802958700002202976700002502998700002003023700002303043700002003066700002603086700002003112700001903132700002203151700002203173700002003195700002303215700002103238700001803259700002403277710003503301856014203336       2024                        eng d  a1664-322400aDrug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.0 aDrugtarget identification in COVID19 disease mechanisms using co  c2023  a12828590 v143 a<p><b>INTRODUCTION: </b>The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.</p><p><b>METHODS: </b>Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.</p><p><b>RESULTS: </b>Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.</p><p><b>DISCUSSION: </b>The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.</p>10aComputer Simulation10aCOVID-1910adrug repositioning10aHumans10aSARS-CoV-210aSystems biology1 aNiarakis, Anna1 aOstaszewski, Marek1 aMazein, Alexander1 aKuperstein, Inna1 aKutmon, Martina1 aGillespie, Marc, E1 aFunahashi, Akira1 aAcencio, Marcio, Luis1 aHemedan, Ahmed1 aAichem, Michael1 aKlein, Karsten1 aCzauderna, Tobias1 aBurtscher, Felicia1 aYamada, Takahiro, G1 aHiki, Yusuke1 aHiroi, Noriko, F1 aHu, Finterly1 aPham, Nhung1 aEhrhart, Friederike1 aWillighagen, Egon, L1 aValdeolivas, Alberto1 aDugourd, Aurélien1 aMessina, Francesco1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aSoliman, Sylvain1 aAghamiri, Sara, Sadat1 aPuniya, Bhanwar, Lal1 aNaldi, Aurélien1 aHelikar, Tomáš1 aSingh, Vidisha1 aFernández, Marco, Fariñas1 aBermudez, Viviam1 aTsirvouli, Eirini1 aMontagud, Arnau1 aNoël, Vincent1 aPonce-de-Leon, Miguel1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aLuna, Augustin1 aPiñero, Janet1 aFurlong, Laura, I1 aBalaur, Irina1 aRougny, Adrien1 aJarosz, Yohan1 aOverall, Rupert, W1 aPhair, Robert1 aPerfetto, Livia1 aMatthews, Lisa1 aRex, Devasahayam, Arokia Bal1 aOrlic-Milacic, Marija1 aGomez, Luis, Cristobal1 aDe Meulder, Bertrand1 aRavel, Jean, Marie1 aJassal, Bijay1 aSatagopam, Venkata1 aWu, Guanming1 aGolebiewski, Martin1 aGawron, Piotr1 aCalzone, Laurence1 aBeckmann, Jacques, S1 aEvelo, Chris, T1 aD'Eustachio, Peter1 aSchreiber, Falk1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aKuiper, Martin1 aValencia, Alfonso1 aWolkenhauer, Olaf1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community  uhttp://clinbioinfosspa.es/content/drug-target-identification-covid-19-disease-mechanisms-using-computational-systems-biology-approaches-004049nas a2200517   4500008004100000022001400041245010200055210006900157260001600226300001300242490000700255520251300262653001502775653001002790653000902800653002202809653002602831653002902857653002502886653001002911653002102921653001802942653003102960653001702991653001103008653001303019653001103032653001103043653000903054653003203063653001603095653001403111653001003125653001703135653001603152100003103168700002903199700003303228700003003261700002103291700001703312700002003329700002003349700003403369856012803403       2024                        eng d  a2165-049700aGenotypic characterization and antimicrobial susceptibility of human  isolates in Southern Spain.0 aGenotypic characterization and antimicrobial susceptibility of h  c2024 Oct 03  ae01028240 v123 a<p> is the main cause of bacterial gastroenteritis and a public health problem worldwide. Little information is available on the genotypic characteristics of human  in Spain. This study is based on an analysis of the resistome, virulome, and phylogenetic relationship, antibiogram prediction, and antimicrobial susceptibility of 114 human isolates of  from a tertiary hospital in southern Spain from October 2020 to June 2023. The isolates were sequenced using Illumina technology, and a bioinformatic analysis was subsequently performed. The susceptibility of  isolates to ciprofloxacin, tetracycline, and erythromycin was also tested. The resistance rates for each antibiotic were 90.3% for ciprofloxacin, 66.7% for tetracycline, and 0.88% for erythromycin. The fluoroquinolone resistance rate obtained is well above the European average (69.1%). CC-21 ( = 23), ST-572 ( = 13), and ST-6532 ( = 13) were the most prevalent clonal complexes (CCs) and sequence types (STs). In the virulome, the , and  genes were detected in all the isolates. A prevalence of 20.1% was obtained for the genes  and , which are related to the pathogenesis of Guillain-Barré syndrome (GBS). The prevalence of the main antimicrobial resistance markers detected were CmeABC (92.1%), RE-cmeABC (7.9%), the T86I substitution in  (88.9%),  (72.6%) (65.8%), and  (17.1%). High antibiogram prediction rates (>97%) were obtained, except for in the case of the erythromycin-resistant phenotype. This study contributes significantly to the knowledge of  genomics for the prevention, treatment, and control of infections caused by this pathogen.IMPORTANCEDespite being the pathogen with the greatest number of gastroenteritis cases worldwide,  remains a poorly studied microorganism. A sustained increase in fluoroquinolone resistance in human isolates is a problem when treating  infections. The development of whole genome sequencing (WGS) techniques has allowed us to better understand the genotypic characteristics of this pathogen and relate them to antibiotic resistance phenotypes. These techniques complement the data obtained from the phenotypic analysis of  isolates. The zoonotic transmission of  through the consumption of contaminated poultry supports approaching the study of this pathogen through "One Health" approach. In addition, due to the limited information on the genomic characteristics of  in Spain, this study provides important data and allows us to compare the results with those obtained in other countries.</p>10aAdolescent10aAdult10aAged10aAged, 80 and over10aAnti-Bacterial Agents10aCampylobacter Infections10aCampylobacter jejuni10aChild10aChild, Preschool10aCiprofloxacin10aDrug Resistance, Bacterial10aErythromycin10aFemale10aGenotype10aHumans10aInfant10aMale10aMicrobial Sensitivity Tests10aMiddle Aged10aPhylogeny10aSpain10aTetracycline10aYoung Adult1 aFernández-Palacios, Pablo1 aGalán-Sánchez, Fátima1 aCasimiro-Soriguer, Carlos, S1 aJurado-Tarifa, Estefanía1 aArroyo, Federico1 aLara, María1 aChaves, Alberto1 aDopazo, Joaquin1 aRodriguez-Iglesias, Manuel, A  uhttp://clinbioinfosspa.es/content/genotypic-characterization-and-antimicrobial-susceptibility-human-isolates-southern-spain04177nas a2200709   4500008004100000022001400041245013800055210006900193260001600262300000800278490000700286520187400293653001202167653003802179653002102217653003002238653001102268653004302279653001902322653001102341653001902352653000902371653001402380653001202394653002402406653003302430653001602463653003702479100002002516700003102536700002702567700002402594700002802618700002502646700002702671700002302698700002702721700002802748700001802776700002002794700002802814700002502842700002502867700002402892700002902916700003502945700002102980700003103001700002103032700001903053700002803072700001803100700002203118700002903140700003103169700002303200700002003223700001703243700002803260700002503288856015403313       2024                        eng d  a1420-907100aHMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.0 aHMGA1 regulates trabectedin sensitivity in advanced softtissue s  c2024 May 17  a2190 v813 a<p>HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.</p>10aAnimals10aAntineoplastic Agents, Alkylating10aCell Line, Tumor10aDrug Resistance, Neoplasm10aFemale10aGene Expression Regulation, Neoplastic10aHMGA1a Protein10aHumans10aLeiomyosarcoma10aMice10aPrognosis10aSarcoma10aSignal Transduction10aTOR Serine-Threonine Kinases10aTrabectedin10aXenograft Model Antitumor Assays1 aMoura, David, S1 aMondaza-Hernandez, Jose, L1 aSanchez-Bustos, Paloma1 aPeña-Chilet, Maria1 aCordero-Varela, Juan, A1 aLopez-Alvarez, Maria1 aCarrillo-Garcia, Jaime1 aMartin-Ruiz, Marta1 aRomero-Gonzalez, Pablo1 aRenshaw-Calderon, Marta1 aRamos, Rafael1 aMarcilla, David1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aCastilla-Ramirez, Carolina1 aGutierrez, Antonio1 aDopazo, Joaquin1 aHindi, Nadia1 aGarcia-Foncillas, Jesus1 aMartin-Broto, Javier  uhttp://clinbioinfosspa.es/content/hmga1-regulates-trabectedin-sensitivity-advanced-soft-tissue-sarcoma-sts-spanish-group-research-sarcomas-geis-study01084nas a2200349   4500008004100000022001400041245005600055210004900111260001600160100002300176700002600199700002500225700002300250700003200273700001800305700002100323700002000344700002200364700001900386700002600405700003300431700002400464700002100488700002000509700001600529700001500545700002100560700002000581700002000601700003000621856008300651       2024                        eng d  a1673-852700aThe Iberian Roma Population Variant Server (IRPVS).0 aIberian Roma Population Variant Server IRPVS  c2024 Mar 261 aMavillard, Fabiola1 aPerez-Florido, Javier1 aOrtuno, Francisco, M1 aValladares, Amador1 aÁlvarez-Villegas, Miren, L1 aRoldán, Gema1 aCarmona, Rosario1 aSoriano, Manuel1 aSusarte, Santiago1 aFuentes, Pilar1 aLópez-López, Daniel1 aNuñez-Negrillo, Ana, María1 aCarvajal, Alejandra1 aMorgado, Yolanda1 aArteaga, Daniel1 aUfano, Rosa1 aMir, Pablo1 aGamella, Juan, F1 aDopazo, Joaquin1 aParadas, Carmen1 aCabrera-Serrano, Macarena  uhttp://clinbioinfosspa.es/content/iberian-roma-population-variant-server-irpvs03334nas a2200445   4500008004100000022001400041245013500055210006900190260001600259300001000275490000700285520187800292653001202170653003102182653002202213653001302235653001102248653001502259653002202274653002802296100003302324700002602357700002302383700001702406700001902423700003302442700001802475700002202493700002702515700002202542700002602564700002002590700001902610700002002629700002802649700002302677700002002700700002002720856014802740       2024                        eng d  a2045-232200aThe integrated genomic surveillance system of Andalusia (SIEGA) provides a One Health regional resource connected with the clinic.0 aintegrated genomic surveillance system of Andalusia SIEGA provid  c2024 Aug 19  a192000 v143 a<p>The One Health approach, recognizing the interconnectedness of human, animal, and environmental health, has gained significance amid emerging zoonotic diseases and antibiotic resistance concerns. This paper aims to demonstrate the utility of a collaborative tool, the SIEGA, for monitoring infectious diseases across domains, fostering a comprehensive understanding of disease dynamics and risk factors, highlighting the pivotal role of One Health surveillance systems. Raw whole-genome sequencing is processed through different species-specific open software that additionally reports the presence of genes associated to anti-microbial resistances and virulence. The SIEGA application is a Laboratory Information Management System, that allows customizing reports, detect transmission chains, and promptly alert on alarming genetic similarities. The SIEGA initiative has successfully accumulated a comprehensive collection of more than 1900 bacterial genomes, including Salmonella enterica, Listeria monocytogenes, Campylobacter jejuni, Escherichia coli, Yersinia enterocolitica and Legionella pneumophila, showcasing its potential in monitoring pathogen transmission, resistance patterns, and virulence factors. SIEGA enables customizable reports and prompt detection of transmission chains, highlighting its contribution to enhancing vigilance and response capabilities. Here we show the potential of genomics in One Health surveillance when supported by an appropriate bioinformatic tool. By facilitating precise disease control strategies and antimicrobial resistance management, SIEGA enhances global health security and reduces the burden of infectious diseases. The integration of health data from humans, animals, and the environment, coupled with advanced genomics, underscores the importance of a holistic One Health approach in mitigating health threats.</p>10aAnimals10aDrug Resistance, Bacterial10aGenome, Bacterial10aGenomics10aHumans10aOne Health10aVirulence Factors10aWhole Genome Sequencing1 aCasimiro-Soriguer, Carlos, S1 aPerez-Florido, Javier1 aRobles, Enrique, A1 aLara, María1 aAguado, Andrea1 aIglesias, Manuel, A Rodrígu1 aLepe, Jose, A1 aGarcía, Federico1 aPérez-Alegre, Mónica1 aAndújar, Eloísa1 aJiménez, Victoria, E1 aCamino, Lola, P1 aLoruso, Nicola1 aAmeyugo, Ulises1 aVazquez, Isabel, María1 aLozano, Carlota, M1 aChaves, Alberto1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/integrated-genomic-surveillance-system-andalusia-siega-provides-one-health-regional-resource-connected-clinic03598nas a2200277   4500008004100000022001400041245013400055210006900189260001600258300000800274490000700282520262900289653001202918653000902930653002502939653002402964100002702988700002003015700001603035700002003051700003103071700002003102700002003122700002403142856015403166       2024                        eng d  a1479-587600aThe mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.0 amechanistic functional landscape of retinitis pigmentosa a machi  c2024 Feb 06  a1390 v223 a<p><b>BACKGROUND: </b>Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.</p><p><b>METHODS: </b>By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa.</p><p><b>RESULTS: </b>A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.</p><p><b>CONCLUSIONS: </b>The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.</p>10aAnimals10aMice10aRetinitis pigmentosa10aSignal Transduction1 aEsteban-Medina, Marina1 aLoucera, Carlos1 aRian, Kinza1 aVelasco, Sheyla1 aOlivares-González, Lorena1 aRodrigo, Regina1 aDopazo, Joaquin1 aPeña-Chilet, Maria  uhttp://clinbioinfosspa.es/content/mechanistic-functional-landscape-retinitis-pigmentosa-machine-learning-driven-approach-therapeutic-target-discovery02738nas a2200313   4500008004100000022001400041245009700055210006900152260001300221300001000234490000600244520172000250100003301970700002602003700001702029700002802046700002302074700002602097700002302123700001702146700002002163700002002183700002802203700002002231700001802251700002002269700002202289856011302311       2024                        eng d  a2398-883500aMolecular and phylogenetic characterization of the monkeypox outbreak in the South of Spain.0 aMolecular and phylogenetic characterization of the monkeypox out  c2024 Mar  ae19650 v73 a<p><b>BACKGROUND AND AIM: </b>Until the May 2022 Monkeypox (MPXV) outbreak, which spread rapidly to many non-endemic countries, the virus was considered a viral zoonosis limited to some African countries. The Andalusian circuit of genomic surveillance was rapidly applied to characterize the MPXV outbreak in the South of Spain.</p><p><b>METHODS: </b>Whole genome sequencing was used to obtain the genomic profiles of samples collected across the south of Spain, representative of all the provinces of Andalusia. Phylogenetic analysis was used to study the relationship of the isolates and the available sequences of the 2022 outbreak.</p><p><b>RESULTS: </b>Whole genome sequencing of a total of 160 MPXV viruses from the different provinces that reported cases were obtained. Interestingly, we report the sequences of MPXV viruses obtained from two patients who died. While one of the isolates bore no noteworthy mutations that explain a potential heightened virulence, in another patient the second consecutive genome sequence, performed after the administration of tecovirimat, uncovered a mutation within the A0A7H0DN30 gene, known to be a prime target for tecovirimat in its Vaccinia counterpart. In general, a low number of mutations were observed in the sequences reported, which were very similar to the reference of the 2022 outbreak (OX044336), as expected from a DNA virus. The samples likely correspond to several introductions of the circulating MPXV viruses from the last outbreak. The virus sequenced from one of the two patients that died presented a mutation in a gene that bears potential connections to drug resistance. This mutation was absent in the initial sequencing before treatment.</p>1 aCasimiro-Soriguer, Carlos, S1 aPerez-Florido, Javier1 aLara, María1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 aPupo-Ledo, Inmaculada1 ade Salazar, Adolfo1 aFuentes, Ana1 aViñuela, Laura1 aChueca, Natalia1 aMartinez-Martinez, Luis1 aLorusso, Nicola1 aLepe, Jose, A1 aDopazo, Joaquin1 aGarcía, Federico  uhttp://clinbioinfosspa.es/content/molecular-and-phylogenetic-characterization-monkeypox-outbreak-south-spain02754nas a2200265   4500008004100000022001400041245011700055210006900172260001600241520176800257100003002025700002102055700002002076700002302096700002302119700001902142700002602161700002602187700003302213700002302246700002002269700003602289700002202325856014102347       2024                        eng d  a1476-557800aMutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.0 aMutational landscape of risk variants in comorbid depression and  c2024 May 283 a<p>Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.</p>1 aPérez-Gutiérrez, Ana, M1 aCarmona, Rosario1 aLoucera, Carlos1 aCervilla, Jorge, A1 aGutiérrez, Blanca1 aMolina, Esther1 aLópez-López, Daniel1 aPerez-Florido, Javier1 aZarza-Rebollo, Juan, Antonio1 aLópez-Isac, Elena1 aDopazo, Joaquin1 aMartinez-Gonzalez, Luis, Javier1 aRivera, Margarita  uhttp://clinbioinfosspa.es/content/mutational-landscape-risk-variants-comorbid-depression-and-obesity-next-generation-sequencing-approach02883nas a2200457   4500008004100000022001400041245011500055210006900170260001600239300001200255490000700267520134200274653003101616653001101647653003101658653003601689653003801725653002301763653001101786653000901797653001601806653003601822653003401858653005101892653002801943100002001971700002701991700002202018700002302040700002502063700001802088700001702106700002002123700002502143700003102168700001802199700001702217700002802234700002502262856013802287       2024                        eng d  a1468-624400aShared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).0 aShared germline genomic variants in two patients with double pri  c2024 Sep 24  a927-9340 v613 a<p><b>BACKGROUND: </b>Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in  and  genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.</p><p><b>METHODS: </b>Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.</p><p><b>RESULTS: </b>Both patients harbouring low-risk GISTs with different mutations ( and ) shared homozygous germline pathogenic deletions in both  and  genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as . No particular pathogenic SNV shared by both patients was detected.</p><p><b>CONCLUSION: </b>Our study provides new insights into germline variants that can be associated with the development of GISTs, namely,  and  deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.</p>10aDNA Copy Number Variations10aFemale10aGastrointestinal Neoplasms10aGastrointestinal Stromal Tumors10aGenetic Predisposition to Disease10aGerm-Line Mutation10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProto-Oncogene Proteins c-kit10aReceptor, Platelet-Derived Growth Factor alpha10aWhole Genome Sequencing1 aMoura, David, S1 aLópez, Daniel, López1 adi Lernia, Davide1 aMartin-Ruiz, Marta1 aLopez-Alvarez, Maria1 aRamos, Rafael1 aMerino, Jose1 aDopazo, Joaquin1 aLopez-Guerrero, Jose1 aMondaza-Hernandez, Jose, L1 aRomero, Pablo1 aHindi, Nadia1 aGarcia-Foncillas, Jesus1 aMartin-Broto, Javier  uhttp://clinbioinfosspa.es/content/shared-germline-genomic-variants-two-patients-double-primary-gastrointestinal-stromal-tumours-gists02245nas a2200253   4500008004100000022001400041245013700055210006900192260001600261490000700277520134400284100002701628700002001655700002401675700002601699700001801725700001801743700002101761700001901782700002801801700002001829700002601849856011601875       2023                        eng d  a1999-492300aA Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.0 aComprehensive Analysis of 21 Actionable Pharmacogenes in the Spa  c2023 Apr 190 v153 a<p>The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.</p>1 aNúñez-Torres, Rocío1 aPita, Guillermo1 aPeña-Chilet, Maria1 aLópez-López, Daniel1 aZamora, Jorge1 aRoldán, Gema1 aHerráez, Belén1 aAlvarez, Nuria1 aAlonso, María, Rosario1 aDopazo, Joaquin1 aGonzález-Neira, Anna  uhttp://clinbioinfosspa.es/content/comprehensive-analysis-21-actionable-pharmacogenes-spanish-population-genetic01707nas a2200169   4500008004100000022001400041245008500055210006900140260001600209490000700225520110800232100001801340700002001358700002401378700002001402856011501422       2023                        eng d  a1422-006700aCrosstalk between Metabolite Production and Signaling Activity in Breast Cancer.0 aCrosstalk between Metabolite Production and Signaling Activity i  c2023 Apr 180 v243 a<p>The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.</p>1 aCubuk, Cankut1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/crosstalk-between-metabolite-production-and-signaling-activity-breast-cancer02663nas a2200301   4500008004100000022001400041245008600055210006900141260001600210300000700226490000700233520168700240100002601927700001801953700002901971700002302000700002102023700002102044700002602065700002202091700002002113700002702133700002602160700002402186700002002210710002902230856010202259       2023                        eng d  a1479-736400aA crowdsourcing database for the copy-number variation of the Spanish population.0 acrowdsourcing database for the copynumber variation of the Spani  c2023 Mar 09  a200 v173 a<p><b>BACKGROUND: </b>Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.</p><p><b>RESULTS: </b>Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .</p><p><b>CONCLUSION: </b>SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.</p>1 aLópez-López, Daniel1 aRoldán, Gema1 aFernandez-Rueda, Jose, L1 aBostelmann, Gerrit1 aCarmona, Rosario1 aAquino, Virginia1 aPerez-Florido, Javier1 aOrtuno, Francisco1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aGonzález-Neira, Anna1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCSVS Crowdsourcing Group  uhttp://clinbioinfosspa.es/content/crowdsourcing-database-copy-number-variation-spanish-population02229nas a2200325   4500008004100000022001400041245014800055210006900203260001600272300001100288490000700299520106600306100002701372700003201399700002401431700001701455700002601472700001901498700002101517700001801538700002201556700001701578700001901595700002901614700002001643700002301663700002301686700002401709856017001733       2023                        eng d  a2211-124700aDefective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.0 aDefective extracellular matrix remodeling in brown adipose tissu  c2023 Jun 13  a1126400 v423 a<p>The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.</p>1 aPellegrinelli, Vanessa1 aFigueroa-Juárez, Elizabeth1 aSamuelson, Isabella1 aU-Din, Mueez1 aRodriguez-Fdez, Sonia1 aVirtue, Samuel1 aLeggat, Jennifer1 aCubuk, Cankut1 aPeirce, Vivian, J1 aNiemi, Tarja1 aCampbell, Mark1 aRodriguez-Cuenca, Sergio1 aDopazo, Joaquin1 aCarobbio, Stefania1 aVirtanen, Kirsi, A1 aVidal-Puig, Antonio  uhttp://clinbioinfosspa.es/content/defective-extracellular-matrix-remodeling-brown-adipose-tissue-associated-fibro-inflammation-and-reduced-diet-induced-thermogenesis02368nas a2200337   4500008004100000022001400041245017900055210006900234260001600303490000700319520115700326100002601483700003301509700002201542700002901564700001901593700001701612700002101629700003401650700002801684700002301712700002601735700002301761700002001784700001701804700002001821700002201841700002001863700001801883856012901901       2023                        eng d  a1422-006700aDetection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.0 aDetection of High Level of CoInfection and the Emergence of Nove  c2023 Jan 260 v243 a<p>Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.</p>1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco1 aFernandez-Rueda, Jose, L1 aAguado, Andrea1 aLara, María1 aRiazzo, Cristina1 aRodriguez-Iglesias, Manuel, A1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 aPupo-Ledo, Inmaculada1 ade Salazar, Adolfo1 aViñuela, Laura1 aFuentes, Ana1 aChueca, Natalia1 aGarcía, Federico1 aDopazo, Joaquin1 aLepe, Jose, A  uhttp://clinbioinfosspa.es/content/detection-high-level-co-infection-and-emergence-novel-sars-cov-2-delta-omicron-and-omicron00614nas a2200169   4500008004100000022001400041245009200055210006900147260000900216300001200225490000700237100002200244700002000266700001900286700002000305856011900325       2023                        eng d  a1664-802100aEditorial: Critical assessment of massive data analysis (CAMDA) annual conference 2021.0 aEditorial Critical assessment of massive data analysis CAMDA ann  c2023  a11543980 v141 aŁabaj, Paweł, P1 aDopazo, Joaquin1 aXiao, Wenzhong1 aKreil, David, P  uhttp://clinbioinfosspa.es/content/editorial-critical-assessment-massive-data-analysis-camda-annual-conference-202102288nas a2200301   4500008004100000022001400041245015200055210006900207260001600276300000900292490000800301520121000309653001201519653001301531653002101544653001101565653004001576653001501616653003201631100002601663700002301689700001701712700002001729700002601749700002001775700002201795856016901817       2023                        eng d  a1469-440900aEvaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice.0 aEvaluation of a combined detection of SARSCoV2 and its variants   c2023 Nov 24  ae2010 v1513 a<p>This study aimed to assess the ability of a real-time reverse transcription polymerase chain reaction (RT-PCR) with multiple targets to detect SARS-CoV-2 and its variants in a single test. Nasopharyngeal specimens were collected from patients in Granada, Spain, between January 2021 and December 2022. Five allele-specific RT-PCR kits were used sequentially, with each kit designed to detect a predominant variant at the time. When the Alpha variant was dominant, the kit included the HV69/70 deletion, E and N genes. When Delta replaced Alpha, the kit incorporated the L452R mutation in addition to E and N genes. When Omicron became dominant, L452R was replaced with the N679K mutation. Before incorporating each variant kit, a comparative analysis was carried out with SARS-CoV-2 whole genome sequencing (WGS). The results demonstrated that RT-PCR with multiple targets can provide rapid and effective detection of SARS-CoV-2 and its variants in a single test. A very high degree of agreement (96.2%) was obtained between the comparison of RT-PCR and WGS. Allele-specific RT-PCR assays make it easier to implement epidemiological surveillance systems for effective public health decision making.</p>10aAlleles10aCOVID-1910aCOVID-19 Testing10aHumans10aReal-Time Polymerase Chain Reaction10aSARS-CoV-210aSensitivity and Specificity1 aChaves-Blanco, Lucía1 ade Salazar, Adolfo1 aFuentes, Ana1 aViñuela, Laura1 aPerez-Florido, Javier1 aDopazo, Joaquin1 aGarcía, Federico  uhttp://clinbioinfosspa.es/content/evaluation-combined-detection-sars-cov-2-and-its-variants-using-real-time-allele-specific-pcr-strategy-advantage-clinical-practice02624nas a2200205   4500008004100000022001400041245020600055210006900261260001600330520167600346100002002022700002102042700002302063700003102086700002102117700003202138700002002170700002002190856020802210       2023                        eng d  a1578-898900aEvidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012-2019).0 aEvidence of the association between increased use of direct oral  c2023 Nov 203 a<p><b>BACKGROUND: </b>The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level.</p><p><b>METHODS: </b>All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment.</p><p><b>RESULTS: </b>A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1±10.2 years (49.7% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2-3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events.</p><p><b>CONCLUSIONS: </b>In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.</p>1 aLoucera, Carlos1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aGonzalez-Manzanares, Rafael1 aDopazo, Joaquin1 aAnguita, Manuel  uhttp://clinbioinfosspa.es/content/evidence-association-between-increased-use-direct-oral-anticoagulants-and-reduction-rate-atrial-fibrillation-related-stroke-and-major-bleeding-population-level-2012-201902648nas a2200409   4500008004100000022001400041245014400055210006900199260001600268300000800284490000600292520117700298100002801475700003601503700002001539700001801559700003301577700002901610700003801639700003601677700002601713700003401739700003701773700002701810700002901837700001701866700001901883700002601902700002501928700002001953700001901973700002401992700002902016700003002045700003202075856013102107       2023                        eng d  a2399-364200aMetabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.0 aMetabolic reprogramming by Acly inhibition using SB204990 alters  c2023 Mar 08  a2500 v63 a<p>ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.</p>1 aSola-García, Alejandro1 aCáliz-Molina, María, Ángeles1 aEspadas, Isabel1 aPetr, Michael1 aPanadero-Morón, Concepción1 aGonzález-Morán, Daniel1 aMartín-Vázquez, María, Eugenia1 aNarbona-Pérez, Álvaro, Jesús1 aLópez-Noriega, Livia1 aMartínez-Corrales, Guillermo1 aLópez-Fernández-Sobrino, Raúl1 aCarmona-Marin, Lina, M1 aMartínez-Force, Enrique1 aYanes, Oscar1 aVinaixa, Maria1 aLópez-López, Daniel1 aReyes, José, Carlos1 aDopazo, Joaquin1 aMartín, Franz1 aGauthier, Benoit, R1 aScheibye-Knudsen, Morten1 aCapilla-González, Vivian1 aMartín-Montalvo, Alejandro  uhttp://clinbioinfosspa.es/content/metabolic-reprogramming-acly-inhibition-using-sb-204990-alters-glucoregulation-and-modulates02396nas a2200301   4500008004100000022001400041245012200055210006900177260001600246300001100262520135200273100002301625700002701648700002601675700001801701700002701719700001801746700002101764700002301785700002401808700003201832700002401864700002201888700002001910700001601930700002301946856012501969       2023                        eng d  a1474-972600amicroRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.0 amicroRNAsmediated regulation of insulin signaling in white adipo  c2023 Jul 04  ae139193 a<p>Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.</p>1 aCorrales, Patricia1 aMartin-Taboada, Marina1 aVivas-García, Yurena1 aTorres, Lucia1 aRamirez-Jimenez, Laura1 aLopez, Yamila1 aHorrillo, Daniel1 aVila-Bedmar, Rocio1 aBarber-Cano, Eloisa1 aIzquierdo-Lahuerta, Adriana1 aPeña-Chilet, Maria1 aMartínez, Carmen1 aDopazo, Joaquin1 aRos, Manuel1 aMedina-Gomez, Gema  uhttp://clinbioinfosspa.es/content/micrornas-mediated-regulation-insulin-signaling-white-adipose-tissue-during-aging-role02391nas a2200193   4500008004100000022001400041245017300055210006900228260001600297300001100313520159800324100002301922700003501945700001701980700002101997700002002018700003002038856012902068       2023                        eng d  a1873-642400aPolystyrene nanoplastics affect transcriptomic and epigenomic signatures of human fibroblasts and derived induced pluripotent stem cells: Implications for human health.0 aPolystyrene nanoplastics affect transcriptomic and epigenomic si  c2022 Dec 09  a1208493 a<p>Plastic pollution is increasing at an alarming rate yet the impact of this pollution on human health is poorly understood. Because human induced pluripotent stem cells (hiPSC) are frequently derived from dermal fibroblasts, these cells offer a powerful platform for the identification of molecular biomarkers of environmental pollution in human cells. Here, we describe a novel proof-of-concept for deriving hiPSC from human dermal fibroblasts deliberately exposed to polystyrene (PS) nanoplastic particles; unexposed hiPSC served as controls. In parallel, unexposed hiPSC were exposed to low and high concentrations of PS nanoparticles. Transcriptomic and epigenomic signatures of all fibroblasts and hiPSCs were defined using RNA-seq and whole genome methyl-seq, respectively. Both PS-treated fibroblasts and derived hiPSC showed alterations in expression of ESRRB and HNF1A genes and circuits involved in the pluripotency of stem cells, as well as in pathways involved in cancer, inflammatory disorders, gluconeogenesis, carbohydrate metabolism, innate immunity, and dopaminergic synapse. Similarly, the expression levels of identified key transcriptional and DNA methylation changes (DNMT3A, ESSRB, FAM133CP, HNF1A, SEPTIN7P8, and TTC34) were significantly affected in both PS-exposed fibroblasts and hiPSC. This study illustrates the power of human cellular models of environmental pollution to narrow down and prioritize the list of candidate molecular biomarkers of environmental pollution. This knowledge will facilitate the deciphering of the origins of environmental diseases.</p>1 aStojkovic, Miodrag1 aGuzmán, Francisco, Manuel Ort1 aHan, Dongjun1 aStojkovic, Petra1 aDopazo, Joaquin1 aStankovic, Konstantina, M  uhttp://clinbioinfosspa.es/content/polystyrene-nanoplastics-affect-transcriptomic-and-epigenomic-signatures-human-fibroblasts03351nas a2200265   4500008004100000022001400041245012500055210006900180260001600249300000800265490000600273520241900279100001802698700001902716700003602735700002902771700002702800700002002827700001802847700002002865700002002885700003102905700001902936856013002955       2023                        eng d  a2058-771600aRapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.0 aRapid degeneration of iPSCderived motor neurons lacking Gdap1 en  c2023 Jul 01  a2170 v93 a<p>Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.</p>1 aLeón, Marian1 aPrieto, Javier1 aMolina-Navarro, María, Micaela1 aGarcia-Garcia, Francisco1 aBarneo-Muñoz, Manuela1 aPonsoda, Xavier1 aSáez, Rosana1 aPalau, Francesc1 aDopazo, Joaquin1 aBelmonte, Juan, Carlos Izp1 aTorres, Josema  uhttp://clinbioinfosspa.es/content/rapid-degeneration-ipsc-derived-motor-neurons-lacking-gdap1-engages-mitochondrial-sustained02334nas a2200229   4500008004100000022001400041245013100055210006900186260001600255300000800271490000700279520147800286100002001764700002101784700002701805700002301832700003101855700002101886700002401907700002001931856015301951       2023                        eng d  a1743-422X00aReal-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.0 aRealworld evidence with a retrospective cohort of 15968 COVID19   c2023 Oct 06  a2260 v203 a<p><b>PURPOSE: </b>Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.</p><p><b>METHODS: </b>Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.</p><p><b>RESULTS: </b>Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.</p><p><b>CONCLUSIONS: </b>In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.</p>1 aLoucera, Carlos1 aCarmona, Rosario1 aEsteban-Medina, Marina1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/real-world-evidence-retrospective-cohort-15968-covid-19-hospitalized-patients-suggests-21-new-effective-treatments02197nas a2200181   4500008004100000022001400041245011200055210006900167260001600236490000700252520151000259100002001769700002201789700003501811700002001846700002001866856012901886       2023                        eng d  a2079-773700aSigPrimedNet: A Signaling-Informed Neural Network for scRNA-seq Annotation of Known and Unknown Cell Types.0 aSigPrimedNet A SignalingInformed Neural Network for scRNAseq Ann  c2023 Apr 100 v123 a<p>Single-cell RNA sequencing is increasing our understanding of the behavior of complex tissues or organs, by providing unprecedented details on the complex cell type landscape at the level of individual cells. Cell type definition and functional annotation are key steps to understanding the molecular processes behind the underlying cellular communication machinery. However, the exponential growth of scRNA-seq data has made the task of manually annotating cells unfeasible, due not only to an unparalleled resolution of the technology but to an ever-increasing heterogeneity of the data. Many supervised and unsupervised methods have been proposed to automatically annotate cells. Supervised approaches for cell-type annotation outperform unsupervised methods except when new (unknown) cell types are present. Here, we introduce SigPrimedNet an artificial neural network approach that leverages (i) efficient training by means of a sparsity-inducing signaling circuits-informed layer, (ii) feature representation learning through supervised training, and (iii) unknown cell-type identification by fitting an anomaly detection method on the learned representation. We show that SigPrimedNet can efficiently annotate known cell types while keeping a low false-positive rate for unseen cells across a set of publicly available datasets. In addition, the learned representation acts as a proxy for signaling circuit activity measurements, which provide useful estimations of the cell functionalities.</p>1 aGundogdu, Pelin1 aAlamo, Inmaculada1 aNepomuceno-Chamorro, Isabel, A1 aDopazo, Joaquin1 aLoucera, Carlos  uhttp://clinbioinfosspa.es/content/sigprimednet-signaling-informed-neural-network-scrna-seq-annotation-known-and-unknown-cell03070nas a2200325   4500008004100000022001400041245009700055210006900152260000900221300001200230490000600242520201700248100001802265700001802283700001902301700002402320700002702344700003202371700002202403700001502425700002202440700002202462700002202484700002602506700002402532700002002556700002202576700002302598856012302621       2023                        eng d  a2673-764700aVisualization of automatically combined disease maps and pathway diagrams for rare diseases.0 aVisualization of automatically combined disease maps and pathway  c2023  a11015050 v33 a<p> Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower.  In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer.  We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets.  In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.</p>1 aGawron, Piotr1 aHoksza, David1 aPiñero, Janet1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aFernandez-Rueda, Jose, Luis1 aColonna, Vincenza1 aSmula, Ewa1 aHeirendt, Laurent1 aAncien, François1 aGrouès, Valentin1 aSatagopam, Venkata, P1 aSchneider, Reinhard1 aDopazo, Joaquin1 aFurlong, Laura, I1 aOstaszewski, Marek  uhttp://clinbioinfosspa.es/content/visualization-automatically-combined-disease-maps-and-pathway-diagrams-rare-diseases02570nas a2200457   4500008004100000022001400041245008300055210006900138260001600207490000700223520116500230653001301395653001801408653001101426653001301437653001401450653001401464653001501478100002001493700002601513700003301539700002501572700002101597700002301618700003201641700003101673700002101704700002901725700002601754700002001780700002501800700002701825700002801852700002301880700002301903700002001926700001801946700002201964700002001986856010602006       2022                        eng d  a1999-491500aAssessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.0 aAssessing the Impact of SARSCoV2 Lineages and Mutations on Patie  c2022 Aug 270 v143 a<p><b>OBJECTIVES: </b>More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.</p><p><b>METHODS: </b>A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.</p><p><b>RESULTS: </b>A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.</p><p><b>CONCLUSIONS: </b>This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.</p>10aCOVID-1910aGenome, Viral10aHumans10amutation10aPandemics10aPhylogeny10aSARS-CoV-21 aLoucera, Carlos1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMartínez-González, Javier1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aRodríguez-Baño, Jesús1 aRomero-Gómez, Manuel1 aLorusso, Nicola1 aGarcia-León, Javier1 aNavarro-Marí, Jose, M1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 ade Salazar, Adolfo1 aViñuela, Laura1 aLepe, Jose, A1 aGarcía, Federico1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/assessing-impact-sars-cov-2-lineages-and-mutations-patient-survival01965nas a2200157   4500008004100000022001400041245015200055210006900207260001600276520129100292100003001583700002001613700002401633700002001657856013001677       2022                        eng d  a1460-208300aDiscovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling.0 aDiscovering potential interactions between rare diseases and COV  c2022 Jan 123 a<p>Recent studies have demonstrated a relevant role of the host genetics in the COVID-19 prognosis. Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for more than 300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.</p>1 aLópez-Sánchez, Macarena1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/discovering-potential-interactions-between-rare-diseases-and-covid-19-combining-mechanistic02967nas a2200445   4500008004100000022001400041245010400055210006900159260001600228490000700244520152100251653001901772653001301791653001101804653003201815653001501847653002901862653001901891653002401910100002601934700002201960700002801982700003002010700002802040700002702068700002702095700003002122700002802152700002202180700002002202700001602222700001902238700002802257700002202285700001602307700002402323700002402347700002202371856012802393       2022                        eng d  a1422-006700aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.0 aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modu  c2022 Aug 040 v233 a<p>Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.</p>10aBone Neoplasms10aEndoglin10aHumans10aMatrix Metalloproteinase 1410aProteomics10aReceptors, Growth Factor10aSarcoma, Ewing10aSignal Transduction1 aPuerto-Camacho, Pilar1 aDiaz-Martin, Juan1 aOlmedo-Pelayo, Joaquín1 aBolado-Carrancio, Alfonso1 aSalguero-Aranda, Carmen1 aJordán-Pérez, Carmen1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aDelgado-Bellido, Daniel1 aLobo-Selma, Laura1 aDopazo, Joaquin1 aSastre, Ana1 aAlonso, Javier1 aGrünewald, Thomas, G P1 aBernabeu, Carmelo1 aByron, Adam1 aBrunton, Valerie, G1 aAmaral, Ana, Teresa1 ade Alava, Enrique  uhttp://clinbioinfosspa.es/content/endoglin-and-mmp14-contribute-ewing-sarcoma-spreading-modulation-cell-matrix-interactions03518nas a2200553   4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520170300228100002701931700002001958700003101978700002802009700003002037700002502067700001702092700002702109700003202136700002602168700002602194700003502220700003102255700001702286700003102303700003002334700003302364700003302397700003502430700003302465700002502498700003102523700002602554700002502580700002002605700002302625700002302648700002102671700002902692700003102721700002002752700002002772700002102792700002702813710002202840856010202862       2022                        eng d  a1579-212900aIncidence and Prevalence of Children's Diffuse Lung Disease in Spain.0 aIncidence and Prevalence of Childrens Diffuse Lung Disease in Sp  c2022 Jan  a22-290 v583 a<p><b>BACKGROUND: </b>Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.</p><p><b>METHODS: </b>Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.</p><p><b>RESULTS: </b>A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).</p><p><b>CONCLUSIONS: </b>We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.</p>1 aTorrent-Vernetta, Alba1 aGaboli, Mirella1 aCastillo-Corullón, Silvia1 aMondéjar-López, Pedro1 aSantiago, Verónica, Sanz1 aCosta-Colomer, Jordi1 aOsona, Borja1 aTorres-Borrego, Javier1 ade la Serna-Blázquez, Olga1 aAlonso, Sara, Bellón1 aAguilera, Pilar, Caro1 ade Atauri, Álvaro, Gimeno-Dí1 aSoria, Alfredo, Valenzuela1 aAyats, Roser1 ade Vicente, Carlos, Martin1 aGonzález, Valle, Velasco1 aGonzález, José, Domingo Mo1 aCalderín, Elisa, María Can1 aPastor-Vivero, María, Dolores1 aÁlvarez, María, Ángeles V1 aRovira-Amigo, Sandra1 aSerrano, Ignacio, Iglesias1 aIzquierdo, Ana, Díez1 aMessa, Inés, de Mir1 aGartner, Silvia1 aNavarro, Alexandra1 aBaz-Redón, Noelia1 aCarmona, Rosario1 aCamats-Tarruella, Núria1 aFernández-Cancio, Mónica1 aRapp, Christina1 aDopazo, Joaquin1 aGriese, Matthias1 aMoreno-Galdó, Antonio1 aChILD-Spain Group  uhttp://clinbioinfosspa.es/content/incidence-and-prevalence-childrens-diffuse-lung-disease-spain-003231nas a2200193   4500008004100000022001400041245011800055210006900173260001600242300000600258490000700264520252200271100002002793700002002813700003002833700002002863700002302883856013102906       2022                        eng d  a1756-038100aIntegrating pathway knowledge with deep neural networks to reduce the dimensionality in single-cell RNA-seq data.0 aIntegrating pathway knowledge with deep neural networks to reduc  c2022 Jan 03  a10 v153 a<p><b>BACKGROUND: </b>Single-cell RNA sequencing (scRNA-seq) data provide valuable insights into cellular heterogeneity which is significantly improving the current knowledge on biology and human disease. One of the main applications of scRNA-seq data analysis is the identification of new cell types and cell states. Deep neural networks (DNNs) are among the best methods to address this problem. However, this performance comes with the trade-off for a lack of interpretability in the results. In this work we propose an intelligible pathway-driven neural network to correctly solve cell-type related problems at single-cell resolution while providing a biologically meaningful representation of the data.</p><p><b>RESULTS: </b>In this study, we explored the deep neural networks constrained by several types of prior biological information, e.g. signaling pathway information, as a way to reduce the dimensionality of the scRNA-seq data. We have tested the proposed biologically-based architectures on thousands of cells of human and mouse origin across a collection of public datasets in order to check the performance of the model. Specifically, we tested the architecture across different validation scenarios that try to mimic how unknown cell types are clustered by the DNN and how it correctly annotates cell types by querying a database in a retrieval problem. Moreover, our approach demonstrated to be comparable to other less interpretable DNN approaches constrained by using protein-protein interactions gene regulation data. Finally, we show how the latent structure learned by the network could be used to visualize and to interpret the composition of human single cell datasets.</p><p><b>CONCLUSIONS: </b>Here we demonstrate how the integration of pathways, which convey fundamental information on functional relationships between genes, with DNNs, that provide an excellent classification framework, results in an excellent alternative to learn a biologically meaningful representation of scRNA-seq data. In addition, the introduction of prior biological knowledge in the DNN reduces the size of the network architecture. Comparative results demonstrate a superior performance of this approach with respect to other similar approaches. As an additional advantage, the use of pathways within the DNN structure enables easy interpretability of the results by connecting features to cell functionalities by means of the pathway nodes, as demonstrated with an example with human melanoma tumor cells.</p>1 aGundogdu, Pelin1 aLoucera, Carlos1 aAlamo-Alvarez, Inmaculada1 aDopazo, Joaquin1 aNepomuceno, Isabel  uhttp://clinbioinfosspa.es/content/integrating-pathway-knowledge-deep-neural-networks-reduce-dimensionality-single-cell-rna-seq03086nas a2200241   4500008004100000022001400041245013700055210006900192260001600261300001000277490000700287520215900294100002402453700003202477700003202509700002102541700002102562700002602583700004102609700002002650700004302670856013102713       2022                        eng d  a2045-232200aProtein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.0 aProtein and functional isoform levels and genetic variants of th  c2022 Jul 02  a112190 v123 a<p>Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.</p>1 aOrtiz-Aljaro, Pilar1 aMontes-Cano, Marco, Antonio1 aGarcía-Lozano, José-Raúl1 aAquino, Virginia1 aCarmona, Rosario1 aPerez-Florido, Javier1 aGarcía-Hernández, Francisco, José1 aDopazo, Joaquin1 aGonzález-Escribano, María, Francisca  uhttp://clinbioinfosspa.es/content/protein-and-functional-isoform-levels-and-genetic-variants-baff-and-april-pathway-components02048nas a2200181   4500008004100000022001400041245013200055210006900187260001600256300000800272490000700280520135300287100003301640700002001673700002401693700002001717856012901737       2022                        eng d  a2045-232200aTowards a metagenomics machine learning interpretable model for understanding the transition from adenoma to colorectal cancer.0 aTowards a metagenomics machine learning interpretable model for   c2022 Jan 10  a4500 v123 a<p>Gut microbiome is gaining interest because of its links with several diseases, including colorectal cancer (CRC), as well as the possibility of being used to obtain non-intrusive predictive disease biomarkers. Here we performed a meta-analysis of 1042 fecal metagenomic samples from seven publicly available studies. We used an interpretable machine learning approach based on functional profiles, instead of the conventional taxonomic profiles, to produce a highly accurate predictor of CRC with better precision than those of previous proposals. Moreover, this approach is also able to discriminate samples with adenoma, which makes this approach very promising for CRC prevention by detecting early stages in which intervention is easier and more effective. In addition, interpretable machine learning methods allow extracting features relevant for the classification, which reveals basic molecular mechanisms accounting for the changes undergone by the microbiome functional landscape in the transition from healthy gut to adenoma and CRC conditions. Functional profiles have demonstrated superior accuracy in predicting CRC and adenoma conditions than taxonomic profiles and additionally, in a context of explainable machine learning, provide useful hints on the molecular mechanisms operating in the microbiota behind these conditions.</p>1 aCasimiro-Soriguer, Carlos, S1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/towards-metagenomics-machine-learning-interpretable-model-understanding-transition-adenoma02333nas a2200373   4500008004100000022001400041245009100055210006900146260001600215300000800231490000700239520108200246653002401328653002601352653002301378653001101401100003001412700002901442700002801471700002801499700003701527700002401564700003101588700001801619700002701637700002501664700003101689700002401720700002001744700002601764700003201790700002501822856011201847       2021                        eng d  a1471-210500aA comprehensive database for integrated analysis of omics data in autoimmune diseases.0 acomprehensive database for integrated analysis of omics data in   c2021 Jun 24  a3430 v223 a<p><b>BACKGROUND: </b>Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.</p><p><b>RESULTS: </b>Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.</p><p><b>CONCLUSIONS: </b>This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.</p>10aAutoimmune Diseases10aComputational Biology10aDatabases, Factual10aHumans1 aMartorell-Marugán, Jordi1 aLópez-Domínguez, Raúl1 aGarcía-Moreno, Adrián1 aToro-Domínguez, Daniel1 aVillatoro-García, Juan, Antonio1 aBarturen, Guillermo1 aMartín-Gómez, Adoración1 aTroule, Kevin1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aGonzález-Rumayor, Víctor1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aSaez-Rodriguez, Julio1 aAlarcón-Riquelme, Marta, E1 aCarmona-Sáez, Pedro  uhttp://clinbioinfosspa.es/content/comprehensive-database-integrated-analysis-omics-data-autoimmune-diseases07188nas a2202077   4500008004100000022001400041245010000055210006900155260001200224300001100236490000700247520130900254653002101563653002601584653002201610653001301632653001401645653001601659653002301675653003101698653003201729653001101761653002301772653002201795653002101817653001601838653003601854653001801890653003201908653001501940653002401955653001301979653002601992653001902018100002302037700001902060700002202079700002102101700001802122700002702140700001902167700002602186700002602212700001802238700001902256700001702275700002202292700002102314700001902335700002902354700001802383700001602401700002902417700001802446700002302464700002202487700002002509700002002529700002702549700002102576700001702597700001802614700002402632700002102656700001602677700002102693700001902714700002302733700002302756700002002779700001702799700001902816700002402835700002102859700002402880700001702904700002302921700002402944700001902968700002002987700001903007700001903026700002903045700002303074700002003097700001703117700001803134700002403152700003303176700002003209700002003229700001603249700001503265700001803280700001903298700002603317700002703343700002003370700002403390700001803414700002403432700002203456700002203478700001903500700002003519700002103539700001803560700001503578700002203593700002303615700001703638700001903655700002403674700001703698700001803715700001703733700002303750700001803773700001803791700002303809700002103832700001703853700002203870700002003892700001803912700001803930700002303948700002103971700002503992700001804017700002004035700001704055700001904072700001704091700002104108700002504129700002704154700002404181700001604205700002104221700002504242700001704267700002004284700001804304700002504322700002404347700002304371700002104394700001904415700002204434700001804456700001604474700002204490700002004512700001804532700002504550700001904575700002204594700002404616700002304640700002004663700002304683700002204706700002304728700002304751700002604774700002004800700002204820700002004842700002304862700002104885700001804906700002404924710003504948856012704983       2021                        eng d  a1744-429200aCOVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.0 aCOVID19 Disease Map a computational knowledge repository of viru  c2021 10  ae103870 v173 a<p>We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.</p>10aAntiviral Agents10aComputational Biology10aComputer Graphics10aCOVID-1910aCytokines10aData Mining10aDatabases, Factual10aGene Expression Regulation10aHost Microbial Interactions10aHumans10aImmunity, Cellular10aImmunity, Humoral10aImmunity, Innate10aLymphocytes10aMetabolic Networks and Pathways10aMyeloid Cells10aProtein Interaction Mapping10aSARS-CoV-210aSignal Transduction10aSoftware10aTranscription Factors10aViral Proteins1 aOstaszewski, Marek1 aNiarakis, Anna1 aMazein, Alexander1 aKuperstein, Inna1 aPhair, Robert1 aOrta-Resendiz, Aurelio1 aSingh, Vidisha1 aAghamiri, Sara, Sadat1 aAcencio, Marcio, Luis1 aGlaab, Enrico1 aRuepp, Andreas1 aFobo, Gisela1 aMontrone, Corinna1 aBrauner, Barbara1 aFrishman, Goar1 aGómez, Luis, Cristóbal1 aSomers, Julia1 aHoch, Matti1 aGupta, Shailendra, Kumar1 aScheel, Julia1 aBorlinghaus, Hanna1 aCzauderna, Tobias1 aSchreiber, Falk1 aMontagud, Arnau1 ade Leon, Miguel, Ponce1 aFunahashi, Akira1 aHiki, Yusuke1 aHiroi, Noriko1 aYamada, Takahiro, G1 aDräger, Andreas1 aRenz, Alina1 aNaveez, Muhammad1 aBocskei, Zsolt1 aMessina, Francesco1 aBörnigen, Daniela1 aFergusson, Liam1 aConti, Marta1 aRameil, Marius1 aNakonecnij, Vanessa1 aVanhoefer, Jakob1 aSchmiester, Leonard1 aWang, Muying1 aAckerman, Emily, E1 aShoemaker, Jason, E1 aZucker, Jeremy1 aOxford, Kristie1 aTeuton, Jeremy1 aKocakaya, Ebru1 aSummak, Gökçe, Yağmur1 aHanspers, Kristina1 aKutmon, Martina1 aCoort, Susan1 aEijssen, Lars1 aEhrhart, Friederike1 aRex, Devasahayam, Arokia Bal1 aSlenter, Denise1 aMartens, Marvin1 aPham, Nhung1 aHaw, Robin1 aJassal, Bijay1 aMatthews, Lisa1 aOrlic-Milacic, Marija1 aRibeiro, Andrea, Senff1 aRothfels, Karen1 aShamovsky, Veronica1 aStephan, Ralf1 aSevilla, Cristoffer1 aVarusai, Thawfeek1 aRavel, Jean-Marie1 aFraser, Rupsha1 aOrtseifen, Vera1 aMarchesi, Silvia1 aGawron, Piotr1 aSmula, Ewa1 aHeirendt, Laurent1 aSatagopam, Venkata1 aWu, Guanming1 aRiutta, Anders1 aGolebiewski, Martin1 aOwen, Stuart1 aGoble, Carole1 aHu, Xiaoming1 aOverall, Rupert, W1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aVega, Carlos1 aGrouès, Valentin1 aVazquez, Miguel1 aPorras, Pablo1 aLicata, Luana1 aIannuccelli, Marta1 aSacco, Francesca1 aNesterova, Anastasia1 aYuryev, Anton1 ade Waard, Anita1 aTurei, Denes1 aLuna, Augustin1 aBabur, Ozgun1 aSoliman, Sylvain1 aValdeolivas, Alberto1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aHelikar, Tomáš1 aPuniya, Bhanwar, Lal1 aModos, Dezso1 aTreveil, Agatha1 aOlbei, Marton1 aDe Meulder, Bertrand1 aBallereau, Stephane1 aDugourd, Aurélien1 aNaldi, Aurélien1 aNoël, Vincent1 aCalzone, Laurence1 aSander, Chris1 aDemir, Emek1 aKorcsmaros, Tamas1 aFreeman, Tom, C1 aAugé, Franck1 aBeckmann, Jacques, S1 aHasenauer, Jan1 aWolkenhauer, Olaf1 aWilighagen, Egon, L1 aPico, Alexander, R1 aEvelo, Chris, T1 aGillespie, Marc, E1 aStein, Lincoln, D1 aHermjakob, Henning1 aD'Eustachio, Peter1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aValencia, Alfonso1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community  uhttp://clinbioinfosspa.es/content/covid19-disease-map-computational-knowledge-repository-virus-host-interaction-mechanisms03503nas a2200709   4500008004100000022001400041245008200055210006900137260001500206300001600221490000700237520139500244653001201639653002301651653001801674653002301692653001001715653001901725653002201744653002501766653001801791653001301809653001101822653001301833653002301846653001301869653001001882100002401892700001801916700002601934700002501960700002101985700002102006700002602027700002002053700002902073700002302102700002902125700002602154700002002180700002702200700002702227700001802254700001902272700003002291700001802321700003402339700001902373700002902392700002702421700001902448700002502467700001702492700002802509700002802537700001902565700002202584700001902606700002002625710004302645856010502688       2021                        eng d  a1362-496200aCSVS, a crowdsourcing database of the Spanish population genetic variability.0 aCSVS a crowdsourcing database of the Spanish population genetic   c2021 01 08  aD1130-D11370 v493 a<p>The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.</p>10aAlleles10aChromosome Mapping10aCrowdsourcing10aDatabases, Genetic10aExome10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aInternet10aPrecision Medicine10aSoftware10aSpain1 aPeña-Chilet, Maria1 aRoldán, Gema1 aPerez-Florido, Javier1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aAquino, Virginia1 aLópez-López, Daniel1 aLoucera, Carlos1 aFernandez-Rueda, Jose, L1 aGallego, Asunción1 aGarcia-Garcia, Francisco1 aGonzález-Neira, Anna1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aSantoyo-López, Javier1 aAyuso, Carmen1 aMinguez, Pablo1 aAvila-Fernandez, Almudena1 aCorton, Marta1 aMoreno-Pelayo, Miguel, Ángel1 aMorin, Matías1 aGallego-Martinez, Alvaro1 aLopez-Escamez, Jose, A1 aBorrego, Salud1 aAntiňolo, Guillermo1 aAmigo, Jorge1 aSalgado-Garrido, Josefa1 aPasalodos-Sanchez, Sara1 aMorte, Beatriz1 aCarracedo, Ángel1 aAlonso, Ángel1 aDopazo, Joaquin1 aSpanish Exome Crowdsourcing Consortium  uhttp://clinbioinfosspa.es/content/csvs-crowdsourcing-database-spanish-population-genetic-variability00616nas a2200157   4500008004100000245013100041210006900172260001600241300000900257490000600266100003100272700002800303700001800331700002000349856008900369       2021                        eng d00aDeciphering Genomic Heterogeneity and the Internal Composition of Tumour Activities through a Hierarchical Factorisation Model0 aDeciphering Genomic Heterogeneity and the Internal Composition o  cJan-11-2021  a28330 v91 aCarbonell-Caballero, José1 aLópez-Quílez, Antonio1 aConesa, David1 aDopazo, Joaquin  uhttps://www.mdpi.com/2227-7390/9/21/2833https://www.mdpi.com/2227-7390/9/21/2833/pdf03078nas a2200493   4500008004100000022001400041245014600055210006900201260001200270300001400282490000700296520140800303100002001711700002401731700002901755700002801784700002501812700002501837700001801862700002401880700002901904700003101933700003501964700002101999700003102020700002102051700001902072700002802091700001802119700003102137700002802168700001702196700003902213700001702252700002502269700002202294700002002316700002302336700001802359700002202377700002902399700002502428856013102453       2021                        eng d  a1878-026100aA DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.0 aDNA damage repair geneassociated signature predicts responses of  c2021 12  a3691-37050 v153 a<p>Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.</p>1 aMoura, David, S1 aPeña-Chilet, Maria1 aVarela, Juan, Antonio Co1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aRamos, Rafael1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aCastilla-Ramirez, Carolina1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aVicioso, Luis1 aBarceló, Jose, Emilio Her1 aRubio-Casadevall, Jordi1 ade Juan, Ana1 aFiaño-Valverde, Maria, Concepcion1 aHindi, Nadia1 aLopez-Alvarez, Maria1 aLacerenza, Serena1 aDopazo, Joaquin1 aGutierrez, Antonio1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aMartin-Broto, Javier  uhttp://clinbioinfosspa.es/content/dna-damage-repair-gene-associated-signature-predicts-responses-patients-advanced-soft-tissue00806nas a2200229   4500008004100000022001300041245014700054210006900201260001600270300001600286490000700302100001600309700002300325700001800348700002200366700002000388700002700408700003000435700002400465700002000489856006700509       2021                        eng d  a2001037000aGenome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data0 aGenomescale mechanistic modeling of signaling pathways made easy  cJan-01-2021  a2968 - 29780 v191 aRian, Kinza1 aHidalgo, Marta, R.1 aCubuk, Cankut1 aFalco, Matias, M.1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttps://linkinghub.elsevier.com/retrieve/pii/S200103702100203800926nas a2200229   4500008004100000022001400041245021100055210006900266260001600335490000700351100002900358700002600387700002000413700003400433700002300467700003100490700003300521700002500554700002000579700001900599856007800618       2021                        eng d  a1868-707500aGenome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract0 aGenomewide analysis of DNA methylation in Hirschsprung enteric p  cJan-12-20210 v131 aVillalba-Benito, Leticia1 aLópez-López, Daniel1 aTorroglosa, Ana1 aCasimiro-Soriguer, Carlos, S.1 aLuzón-Toro, Berta1 aFernández, Raquel, María1 aMoya-Jiménez, María, José1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html02548nas a2200301   4500008004100000022001400041245009700055210006900152260001500221490000700236520154600243653001801789653001401807653001501821653002801836100002501864700002001889700003301909700001801942700002901960700002401989700002302013700002002036700002202056700002602078700002002104856012202124       2021                        eng d  a2047-217X00aHighly accurate whole-genome imputation of SARS-CoV-2 from partial or low-quality sequences.0 aHighly accurate wholegenome imputation of SARSCoV2 from partial   c2021 12 020 v103 a<p><b>BACKGROUND: </b>The current SARS-CoV-2 pandemic has emphasized the utility of viral whole-genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and, therefore, useless sequences. Viral sequences evolve in the context of a complex phylogeny and different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data.</p><p><b>RESULTS: </b>We have developed the impuSARS application, which takes advantage of the enormous number of SARS-CoV-2 genomes available, using a reference panel containing 239,301 sequences, to produce missing data imputation in viral genomes. ImpuSARS was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing), showing great fidelity when reconstructing the original sequences, recovering the lineage with a 100% precision for almost all the lineages, even in very poorly covered genomes (<20%).</p><p><b>CONCLUSIONS: </b>Imputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. ImpuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole-genome sequencing.</p>10aGenome, Viral10aPhylogeny10aSARS-CoV-210aWhole Genome Sequencing1 aOrtuno, Francisco, M1 aLoucera, Carlos1 aCasimiro-Soriguer, Carlos, S1 aLepe, Jose, A1 aMartinez, Pedro, Camacho1 aDiaz, Laura, Merino1 ade Salazar, Adolfo1 aChueca, Natalia1 aGarcía, Federico1 aPerez-Florido, Javier1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/highly-accurate-whole-genome-imputation-sars-cov-2-partial-or-low-quality-sequences02741nas a2200253   4500008004100000022001400041245011600055210006900171260001600240490000700256520183900263100002002102700002402122700002202146700002002168700002802188700002702216700002602243700002902269700002002298700001802318700002602336856012502362       2021                        eng d  a2075-442600aImplementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System.0 aImplementing Personalized Medicine in COVID19 in Andalusia An Op  c2021 May 260 v113 a<p>The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.</p>1 aDopazo, Joaquin1 aMaya-Miles, Douglas1 aGarcía, Federico1 aLorusso, Nicola1 aCalleja, Miguel, Ángel1 aPareja, María, Jesús1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aPadillo, Javier1 aTúnez, Isaac1 aRomero-Gómez, Manuel  uhttp://clinbioinfosspa.es/content/implementing-personalized-medicine-covid-19-andalusia-opportunity-transform-healthcare01572nas a2200253   4500008004100000022001400041245005600055210005300111260001600164300000600180490000700186520083300193100001601026700002701042700002201069700001801091700002101109700002001130700001901150700002301169700002401192700002001216856008201236       2021                        eng d  a1756-038100aMechanistic modeling of the SARS-CoV-2 disease map.0 aMechanistic modeling of the SARSCoV2 disease map  c2021 Jan 21  a50 v143 a<p>Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.</p>1 aRian, Kinza1 aEsteban-Medina, Marina1 aHidalgo, Marta, R1 aCubuk, Cankut1 aFalco, Matias, M1 aLoucera, Carlos1 aGunyel, Devrim1 aOstaszewski, Marek1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/mechanistic-modeling-sars-cov-2-disease-map01933nas a2200277   4500008004100000022001400041245011400055210006900169260001600238490000700254520095600261100002701217700002401244700002601268700003001294700001901324700001901343700003401362700003601396700002001432700002001452700001801472700001701490700002001507856012801527       2021                        eng d  a2072-669400aMutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.0 aMutational Characterization of Cutaneous Melanoma Supports Diver  c2021 Oct 180 v133 a<p>According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.</p>1 aMillán-Esteban, David1 aPeña-Chilet, Maria1 aGarcía-Casado, Zaida1 aManrique-Silva, Esperanza1 aRequena, Celia1 aBañuls, José1 aLopez-Guerrero, Jose, Antonio1 aRodríguez-Hernández, Aranzazu1 aTraves, Víctor1 aDopazo, Joaquin1 aVirós, Amaya1 aKumar, Rajiv1 aNagore, Eduardo  uhttp://clinbioinfosspa.es/content/mutational-characterization-cutaneous-melanoma-supports-divergent-pathways-model-melanoma00782nas a2200229   4500008004100000245009000041210006900131260001600200300000800216490000700224100003400231700002600265700003000291700002600321700002700347700002000374700003600394700002800430700002000458700002900478856004500507       2021                        eng d00aPhylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)0 aPhylogenetic Analysis of the 2020 West Nile Virus WNV Outbreak i  cJan-05-2021  a8360 v131 aCasimiro-Soriguer, Carlos, S.1 aPerez-Florido, Javier1 aFernandez-Rueda, Jose, L.1 aPedrosa-Corral, Irene1 aGuillot-Sulay, Vicente1 aLorusso, Nicola1 aMartinez-Gonzalez, Luis, Javier1 aNavarro-Marí, Jose, M.1 aDopazo, Joaquin1 aSanbonmatsu-Gámez, Sara  uhttps://www.mdpi.com/1999-4915/13/5/836 02756nas a2200385   4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012402246       2021                        eng d  a2045-232200aReal world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.0 aReal world evidence of calcifediol or vitamin D prescription and  c2021 12 03  a233800 v113 a<p>COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.</p>10aCalcifediol10aCOVID-1910aFemale10aHumans10aKaplan-Meier Estimate10aMale10aRetrospective Studies10aSpain10aSurvival Analysis10aVitamin D1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aTúnez, Isaac1 aBouillon, Roger1 aDopazo, Joaquin1 aGomez, Jose, Manuel Que  uhttp://clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1905404nas a2201477   4500008004100000022001400041245007800055210006900133260001200202300001400214490000700228520122900235653002601464653001401490653001101504653001501515653003501530653002001565653003801585100001901623700001901642700001801661700002301679700002401702700002301726700002101749700002801770700001801798700002501816700002401841700002701865700001801892700002301910700002001933700001501953700002201968700002001990700002702010700002102037700002202058700001802080700001902098700002702117700002002144700001902164700002002183700002102203700001702224700002102241700002302262700002002285700002202305700002002327700001802347700002302365700001802388700002102406700002602427700001902453700001702472700001802489700002402507700001902531700001602550700001702566700001602583700002102599700002102620700002102641700002102662700002202683700002202705700002102727700001602748700001702764700001502781700002102796700001702817700002402834700002202858700002002880700002402900700001802924700001602942700002302958700002102981700002403002700001703026700002603043700002403069700002503093700002403118700002203142700002103164700001703185700001903202700001803221700001803239700001303257700001703270700001603287700001903303700002703322700002003349700001703369700002203386700001903408700001903427700002603446700001903472700002903491700002103520700001603541700002203557700001603579700002003595700002403615700001903639700002403658700002203682700002003704700001803724710003303742710004903775856010203824       2021                        eng d  a1546-170X00aReporting guidelines for human microbiome research: the STORMS checklist.0 aReporting guidelines for human microbiome research the STORMS ch  c2021 11  a1885-18920 v273 a<p>The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.</p>10aComputational Biology10aDysbiosis10aHumans10aMicrobiota10aObservational Studies as Topic10aResearch Design10aTranslational Science, Biomedical1 aMirzayi, Chloe1 aRenson, Audrey1 aZohra, Fatima1 aElsafoury, Shaimaa1 aGeistlinger, Ludwig1 aKasselman, Lora, J1 aEckenrode, Kelly1 avan de Wijgert, Janneke1 aLoughman, Amy1 aMarques, Francine, Z1 aMacIntyre, David, A1 aArumugam, Manimozhiyan1 aAzhar, Rimsha1 aBeghini, Francesco1 aBergstrom, Kirk1 aBhatt, Ami1 aBisanz, Jordan, E1 aBraun, Jonathan1 aBravo, Hector, Corrada1 aBuck, Gregory, A1 aBushman, Frederic1 aCasero, David1 aClarke, Gerard1 aCollado, Maria, Carmen1 aCotter, Paul, D1 aCryan, John, F1 aDemmer, Ryan, T1 aDevkota, Suzanne1 aElinav, Eran1 aEscobar, Juan, S1 aFettweis, Jennifer1 aFinn, Robert, D1 aFodor, Anthony, A1 aForslund, Sofia1 aFranke, Andre1 aFurlanello, Cesare1 aGilbert, Jack1 aGrice, Elizabeth1 aHaibe-Kains, Benjamin1 aHandley, Scott1 aHerd, Pamela1 aHolmes, Susan1 aJacobs, Jonathan, P1 aKarstens, Lisa1 aKnight, Rob1 aKnights, Dan1 aKoren, Omry1 aKwon, Douglas, S1 aLangille, Morgan1 aLindsay, Brianna1 aMcGovern, Dermot1 aMcHardy, Alice, C1 aMcWeeney, Shannon1 aMueller, Noel, T1 aNezi, Luigi1 aOlm, Matthew1 aPalm, Noah1 aPasolli, Edoardo1 aRaes, Jeroen1 aRedinbo, Matthew, R1 aRühlemann, Malte1 aSartor, Balfour1 aSchloss, Patrick, D1 aSchriml, Lynn1 aSegal, Eran1 aShardell, Michelle1 aSharpton, Thomas1 aSmirnova, Ekaterina1 aSokol, Harry1 aSonnenburg, Justin, L1 aSrinivasan, Sujatha1 aThingholm, Louise, B1 aTurnbaugh, Peter, J1 aUpadhyay, Vaibhav1 aWalls, Ramona, L1 aWilmes, Paul1 aYamada, Takuji1 aZeller, Georg1 aZhang, Mingyu1 aZhao, Ni1 aZhao, Liping1 aBao, Wenjun1 aCulhane, Aedin1 aDevanarayan, Viswanath1 aDopazo, Joaquin1 aFan, Xiaohui1 aFischer, Matthias1 aJones, Wendell1 aKusko, Rebecca1 aMason, Christopher, E1 aMercer, Tim, R1 aSansone, Susanna-Assunta1 aScherer, Andreas1 aShi, Leming1 aThakkar, Shraddha1 aTong, Weida1 aWolfinger, Russ1 aHunter, Christopher1 aSegata, Nicola1 aHuttenhower, Curtis1 aDowd, Jennifer, B1 aJones, Heidi, E1 aWaldron, Levi1 aGenomic Standards Consortium1 aMassive Analysis and Quality Control Society  uhttp://clinbioinfosspa.es/content/reporting-guidelines-human-microbiome-research-storms-checklist03596nas a2200505   4500008004100000022001400041245013900055210006900194260001500263300000700278490000700285520188200292653001702174653002602191653001402217653003202231653000902263653001102272653001502283653001702298653003202315653002902347653001402376100003502390700003102425700003302456700002002489700001802509700002802527700003202555700002902587700003002616700002602646700001902672700003602691700002202727700002902749700002802778700003102806700002602837700002602863700003302889700004002922856012802962       2021                        eng d  a1528-365800aTaxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.0 aTaxonomic variations in the gut microbiome of gout patients with  c2021 05 24  a500 v273 a<p><b>OBJECTIVE: </b>To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.</p><p><b>METHODS: </b>Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.</p><p><b>RESULTS: </b>We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.</p><p><b>CONCLUSION: </b>Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.</p>10aBiodiversity10aComputational Biology10aDysbiosis10aGastrointestinal Microbiome10aGout10aHumans10aMetagenome10ametagenomics10aProtein Interaction Mapping10aProtein Interaction Maps10aUric Acid1 aMéndez-Salazar, Eder, Orlando1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aCubuk, Cankut1 aZamudio-Cuevas, Yessica1 aFrancisco-Balderas, Adriana1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aLozada-Pérez, Carlos1 aPineda, Carlos1 aSánchez-González, Austreberto1 aSilveira, Luis, H1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Citlalli1 aLagunas-Martínez, Alfredo1 aVazquez-Gomez, Alonso1 aLópez-Reyes, Alberto1 aPalacios-González, Berenice1 aMartínez-Nava, Gabriela, Angélica  uhttp://clinbioinfosspa.es/content/taxonomic-variations-gut-microbiome-gout-patients-and-without-tophi-might-have-functional02115nas a2200409   4500008004100000022001400041245012500055210006900180260001200249300001300261490000700274520080500281653001501086653002101101653002601122653002301148653003001171653001301201653004201214653001101256653002401267653001301291653001201304653002401316653001301340653001801353653002701371653001301398100003101411700002601442700002501468700002401493700002001517700002201537700002001559856012601579       2021                        eng d  a1553-735800aA versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.0 aversatile workflow to integrate RNAseq genomic and transcriptomi  c2021 02  ae10087480 v173 a<p>MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.</p>10aAlgorithms10aCell Line, Tumor10aComputational Biology10aDatabases, Factual10aGene Expression Profiling10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aModels, Theoretical10amutation10aRNA-seq10aSignal Transduction10aSoftware10aTranscriptome10awhole exome sequencing10aWorkflow1 aGarrido-Rodriguez, Martín1 aLópez-López, Daniel1 aOrtuno, Francisco, M1 aPeña-Chilet, Maria1 aMuñoz, Eduardo1 aCalzado, Marco, A1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/versatile-workflow-integrate-rna-seq-genomic-and-transcriptomic-data-mechanistic-models01793nas a2200577   4500008004100000022001400041245011100055210006900166260001500235300000800250490000600258653002000264653002600284653002700310653001300337653002300350653003200373653003100405653001100436653003000447653002300477653001400500653002100514653001500535100002300550700002200573700002300595700002100618700001900639700002300658700002300681700002500704700002000729700001900749700002000768700002100788700001600809700002200825700002200847700002300869700002000892700002700912700002300939700002200962700002100984700002001005700002101025700001801046700002401064856012701088       2020                        eng d  a2052-446300aCOVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.0 aCOVID19 Disease Map building a computational repository of SARSC  c2020 05 05  a1360 v710aBetacoronavirus10aComputational Biology10aCoronavirus Infections10aCOVID-1910aDatabases, Factual10aHost Microbial Interactions10aHost-Pathogen Interactions10aHumans10aInternational Cooperation10aModels, Biological10aPandemics10aPneumonia, Viral10aSARS-CoV-21 aOstaszewski, Marek1 aMazein, Alexander1 aGillespie, Marc, E1 aKuperstein, Inna1 aNiarakis, Anna1 aHermjakob, Henning1 aPico, Alexander, R1 aWillighagen, Egon, L1 aEvelo, Chris, T1 aHasenauer, Jan1 aSchreiber, Falk1 aDräger, Andreas1 aDemir, Emek1 aWolkenhauer, Olaf1 aFurlong, Laura, I1 aBarillot, Emmanuel1 aDopazo, Joaquin1 aOrta-Resendiz, Aurelio1 aMessina, Francesco1 aValencia, Alfonso1 aFunahashi, Akira1 aKitano, Hiroaki1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard  uhttp://clinbioinfosspa.es/content/covid-19-disease-map-building-computational-repository-sars-cov-2-virus-host-interaction01082nas a2200313   4500008004100000022001400041245014500055210006900200260001500269300000800284490000600292653002800298653001300326653002300339653001100362653002100373653003300394653003100427653001300458653001500471653002400486100002000510700002700530700001600557700002100573700002000594700002400614856013000638       2020                        eng d  a2059-363500aDrug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection.0 aDrug repurposing for COVID19 using machine learning and mechanis  c2020 12 11  a2900 v510aComputational Chemistry10aCOVID-1910adrug repositioning10aHumans10aMachine Learning10aMolecular Docking Simulation10aMolecular Targeted Therapy10aProteins10aSARS-CoV-210aSignal Transduction1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aRian, Kinza1 aFalco, Matias, M1 aDopazo, Joaquin1 aPeña-Chilet, Maria  uhttp://clinbioinfosspa.es/content/drug-repurposing-covid-19-using-machine-learning-and-mechanistic-models-signal-transduction03120nas a2200673   4500008004100000022001400041245010800055210006900163260000900232490000600241520108900247653002601336653003101362653004201393653001101435100001901446700002101465700002001486700001901506700003301525700002701558700003501585700002001620700002201640700001201662700001801674700002201692700001301714700002101727700002001748700002101768700001801789700001801807700002601825700001801851700001601869700002401885700001801909700002101927700001701948700002701965700001801992700002302010700001902033700002702052700001402079700002302093700001702116700001902133700001502152700002202167700002102189700002202210700001702232700003202249700001802281700002402299856012302323       2020                        eng d  a2046-140200aThe ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.0 aELIXIR Human Copy Number Variations Community building bioinform  c20200 v93 a<p>Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established   with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.</p>10aComputational Biology10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans1 aSalgado, David1 aArmean, Irina, M1 aBaudis, Michael1 aBeltran, Sergi1 aCapella-Gutíerrez, Salvador1 aCarvalho-Silva, Denise1 aDel Angel, Victoria, Dominguez1 aDopazo, Joaquin1 aFurlong, Laura, I1 aGao, Bo1 aGarcia, Leyla1 aGerloff, Dietlind1 aGut, Ivo1 aGyenesei, Attila1 aHabermann, Nina1 aHancock, John, M1 aHanauer, Marc1 aHovig, Eivind1 aJohansson, Lennart, F1 aKeane, Thomas1 aKorbel, Jan1 aLauer, Katharina, B1 aLaurie, Steve1 aLeskošek, Brane1 aLloyd, David1 aMarqués-Bonet, Tomás1 aMei, Hailiang1 aMonostory, Katalin1 aPiñero, Janet1 aPoterlowicz, Krzysztof1 aRath, Ana1 aSamarakoon, Pubudu1 aSanz, Ferran1 aSaunders, Gary1 aSie, Daoud1 aSwertz, Morris, A1 aTsukanov, Kirill1 aValencia, Alfonso1 aVidak, Marko1 aGonzález, Cristina, Yenyxe1 aYlstra, Bauke1 aBéroud, Christophe  uhttp://clinbioinfosspa.es/content/elixir-human-copy-number-variations-community-building-bioinformatics-infrastructure02417nas a2200481   4500008004100000022001400041245004700055210004600102260001600148300001100164490000700175520106100182100001901243700002701262700001901289700002001308700002201328700002101350700002001371700001901391700002401410700001501434700002501449700002301474700002401497700002001521700002701541700002401568700002001592700002101612700002201633700002201655700002901677700001801706700001301724700001701737700001601754700002001770700002501790700001901815700002601834856007501860       2020                        eng d  a2589-004200aImmune Cell Associations with Cancer Risk.0 aImmune Cell Associations with Cancer Risk  c2020 Jul 24  a1012960 v233 a<p>Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.</p>1 aPalomero, Luis1 aGalván-Femenía, Ivan1 ade Cid, Rafael1 aEspín, Roderic1 aBarnes, Daniel, R1 aBlommaert, Eline1 aGil-Gil, Miguel1 aFalo, Catalina1 aStradella, Agostina1 aOuchi, Dan1 aRoso-Llorach, Albert1 aViolan, Concepció1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aExtremera, Ana, Isabel1 aGarcía-Valero, Mar1 aHerranz, Carmen1 aMateo, Francesca1 aMereu, Elisabetta1 aBeesley, Jonathan1 aChenevix-Trench, Georgia1 aRoux, Cecilia1 aMak, Tak1 aBrunet, Joan1 aHakem, Razq1 aGorrini, Chiara1 aAntoniou, Antonis, C1 aLázaro, Conxi1 aPujana, Miquel, Angel  uhttp://clinbioinfosspa.es/content/immune-cell-associations-cancer-risk01455nas a2200217   4500008004100000022001400041245006500055210006200120260001900182300001200201490000700213520073900220653002200959653001100981100003700992700002901029700003801058700003101096700002001127856009001147       2020                        spa d  a1578-128300a[Impact assessment on data protection in research projects].0 aImpact assessment on data protection in research projects  c2020 Sep - Oct  a521-5230 v343 a<p>Recent changes in European regulations for personal data protection still allow the use of health data for research purposes, but they have set the Impact Assessment on Data Protection as an instrument for reflection and risk analysis in the process of data processing. The publication of a guide for facilitates this impact assessment, although it is not directly applicable to research projects. Experience in a specific project is detailed, showing how the context of the treatment becomes relevant with respect to the data characteristics. Carrying out an impact assessment is an opportunity to ensure compliance with the principles of data protection in an increasingly complex environment with greater ethical challenges.</p>10aComputer Security10aHumans1 aGarcía-León, Francisco, Javier1 aVillegas-Portero, Román1 aGoicoechea-Salazar, Juan, Antonio1 aMuñoyerro-Muñiz, Dolores1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/impact-assessment-data-protection-research-projects00750nas a2200157   4500008004100000245011500041210006900156260001600225490000600241100002100247700002400268700002000292700002200312700002000334856023800354       2020                        eng d00aMechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract0 aMechanistic models of signaling pathways deconvolute the gliobla  cJan-06-20200 v21 aFalco, Matias, M1 aPeña-Chilet, Maria1 aLoucera, Carlos1 aHidalgo, Marta, R1 aDopazo, Joaquin  uhttps://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf02316nas a2200241   4500008004100000022001400041245014100055210006900196260001500265490000600280520146700286653001101753653004301764653001101807653000901818653001401827653002401841100001801865700001801883700002401901700002001925856012901945       2020                        eng d  a2073-440900aMechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments.0 aMechanistic Models of Signaling Pathways Reveal the Drug Action   c2020 06 290 v93 a<p>Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.</p>10aFemale10aGene Expression Regulation, Neoplastic10aHumans10aMale10aNeoplasms10aSignal Transduction1 aCubuk, Cankut1 aCan, Fatma, E1 aPeña-Chilet, Maria1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/mechanistic-models-signaling-pathways-reveal-drug-action-mechanisms-behind-gender-specific03270nas a2200493   4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856012702649       2020                        eng d  a2051-142600aNivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.0 aNivolumab and sunitinib combination in advanced soft tissue sarc  c2020 110 v83 a<p><b>BACKGROUND: </b>Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).</p><p><b>METHODS: </b>This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).</p><p><b>RESULTS: </b>From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).</p><p><b>CONCLUSIONS: </b>Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.</p>10aAdult10aAged10aAntineoplastic Agents, Immunological10aFemale10aHumans10aMale10aMiddle Aged10aNivolumab10aSarcoma10aSunitinib10aYoung Adult1 aMartin-Broto, Javier1 aHindi, Nadia1 aGrignani, Giovanni1 aMartinez-Trufero, Javier1 aRedondo, Andres1 aValverde, Claudia1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aD'Ambrosio, Lorenzo1 aGutierrez, Antonio1 aPerez-Vega, Herminia1 aEncinas-Tobajas, Victor1 ade Alava, Enrique1 aCollini, Paola1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCarrasco-Garcia, Irene1 aLopez-Alvarez, Maria1 aMoura, David, S1 aLopez-Martin, Jose, A  uhttp://clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm05175nas a2201117   4500008004100000022001400041245011300055210006900168260001200237300001200249490000700261520174900268653001402017653003102031653001502062653002502077653001902102653005102121653001102172653002902183653003802212653001102250653000902261653002302270653003602293653002702329100002202356700001702378700002402395700002802419700003302447700002702480700001502507700002402522700002902546700002602575700002802601700001702629700002002646700002102666700001902687700002702706700001902733700002002752700002402772700003002796700001902826700002602845700002902871700001802900700002102918700002202939700003202961700002002993700002603013700002903039700002103068700002203089700002103111700001903132700002703151700002403178700002903202700003203231700002003263700001803283700003103301700002803332700001603360700002503376700003103401700003303432700002903465700002203494700002103516700002403537700001903561700002503580700001703605700001703622700001803639700002303657700002003680700001603700700002203716700002503738700001803763700002303781700002003804700002003824700002103844700003303865700001703898700002103915856012103936       2020                        eng d  a1468-624400aOptimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.0 aOptimised molecular genetic diagnostics of Fanconi anaemia by wh  c2020 04  a258-2680 v573 a<p><b>PURPOSE: </b>Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.</p><p><b>METHODS: </b>68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test  missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.</p><p><b>RESULTS: </b>We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two  variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.</p>10aCell Line10aDNA Copy Number Variations10aDNA Repair10aDNA-Binding Proteins10aFanconi Anemia10aFanconi Anemia Complementation Group A Protein10aFemale10aGene Knockout Techniques10aGenetic Predisposition to Disease10aHumans10aMale10aMutation, Missense10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aBogliolo, Massimo1 aPujol, Roser1 aAza-Carmona, Miriam1 aMuñoz-Subirana, Núria1 aRodriguez-Santiago, Benjamin1 aCasado, José, Antonio1 aRio, Paula1 aBauser, Christopher1 aReina-Castillón, Judith1 aLopez-Sanchez, Marcos1 aGonzalez-Quereda, Lidia1 aGallano, Pia1 aCatalá, Albert1 aRuiz-Llobet, Ana1 aBadell, Isabel1 aDiaz-Heredia, Cristina1 aHladun, Raquel1 aSenent, Leonort1 aArgiles, Bienvenida1 aBurgues, Juan, Miguel Ber1 aBañez, Fatima1 aArrizabalaga, Beatriz1 aAlmaraz, Ricardo, López1 aLopez, Monica1 aFiguera, Ángela1 aMolinés, Antonio1 ade Soto, Inmaculada, Pérez1 aHernando, Inés1 aMuñoz, Juan, Antonio1 aMarin, Maria, Del Rosari1 aBalmaña, Judith1 aStjepanovic, Neda1 aCarrasco, Estela1 aCuesta, Isabel1 aCosuelo, José, Miguel1 aRegueiro, Alexandra1 aJimenez, José, Moraleda1 aGalera-Miñarro, Ana, Maria1 aRosiñol, Laura1 aCarrió, Anna1 aBeléndez-Bieler, Cristina1 aSoto, Antonio, Escudero1 aCela, Elena1 ade la Mata, Gregorio1 aFernández-Delgado, Rafael1 aGarcia-Pardos, Maria, Carmen1 aSáez-Villaverde, Raquel1 aBarragaño, Marta1 aPortugal, Raquel1 aLendinez, Francisco1 aHernadez, Ines1 aVagace, José, Manue1 aTapia, Maria1 aNieto, José1 aGarcia, Marta1 aGonzalez, Macarena1 aVicho, Cristina1 aGalvez, Eva1 aValiente, Alberto1 aAntelo, Maria, Luisa1 aAncliff, Phil1 aGarcía, Francisco1 aDopazo, Joaquin1 aSevilla, Julian1 aPaprotka, Tobias1 aPérez-Jurado, Luis, Alberto1 aBueren, Juan1 aSurralles, Jordi  uhttp://clinbioinfosspa.es/content/optimised-molecular-genetic-diagnostics-fanconi-anaemia-whole-exome-sequencing-and04656nas a2200625   4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856012803902       2020                        eng d  a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu  c2020 03  a456-4660 v213 a<p><b>BACKGROUND: </b>Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia  uhttp://clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial02753nas a2200373   4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520158800253653002801841653001101869653003501880653002401915653001801939653001301957653001701970653001801987653002202005100001702027700002102044700002102065700002002086700002902106700002002135700002202155700002002177700001902197700001702216700002302233856012302256       2020                        eng d  a1549-491800aPlatform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.0 aPlatform to study intracellular polystyrene nanoplastic pollutio  c2020 10 01  a1321-13250 v383 a<p>Increased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.</p>10aEnvironmental Pollution10aHumans10aInduced Pluripotent Stem Cells10aIntracellular Space10aNanoparticles10aPlastics10aPolystyrenes10aTranscriptome10aTreatment Outcome1 aBojic, Sanja1 aFalco, Matias, M1 aStojkovic, Petra1 aLjujic, Biljana1 aJankovic, Marina, Gazdic1 aArmstrong, Lyle1 aMarkovic, Nebojsa1 aDopazo, Joaquin1 aLako, Majlinda1 aBauer, Roman1 aStojkovic, Miodrag  uhttp://clinbioinfosspa.es/content/platform-study-intracellular-polystyrene-nanoplastic-pollution-and-clinical-outcomes02123nas a2200325   4500008004100000022001400041245008900055210006900144260001200213300001400225490000700239520106200246653001801308653003101326653004201357653001101399653003101410653001301441653003901454100002601493700002001519700002101539700002101560700002001581700002001601700002001621700001901641700002001660856011701680       2020                        eng d  a1098-100400aSMN1 copy-number and sequence variant analysis from next-generation sequencing data.0 aSMN1 copynumber and sequence variant analysis from nextgeneratio  c2020 12  a2073-20770 v413 a<p>Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.</p>10aBase Sequence10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans10aReproducibility of Results10aSoftware10aSurvival of Motor Neuron 1 Protein1 aLópez-López, Daniel1 aLoucera, Carlos1 aCarmona, Rosario1 aAquino, Virginia1 aSalgado, Josefa1 aPasalodos, Sara1 aMiranda, María1 aAlonso, Ángel1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/smn1-copy-number-and-sequence-variant-analysis-next-generation-sequencing-data03110nas a2200493   4500008004100000022001400041245014400055210006900199260001500268490000700283520148700290653001201777653003601789653003001825653003101855653001801886653001101904653003601915653000901951653001501960653002401975653003401999653003302033653002402066653000902090653002502099653001502124653001702139653002302156653001802179653003402197653001802231100001802249700002902267700001702296700002402313700002102337700003102358700002002389700002102409700002602430700003402456856012602490       2020                        eng d  a2073-442500aTranscriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.0 aTranscriptomic Analysis of a Diabetic SkinHumanized Mouse Model   c2020 12 310 v123 a<p>Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.</p>10aAnimals10aDiabetes Mellitus, Experimental10aGene Expression Profiling10aGene Expression Regulation10aGene ontology10aHumans10aMetabolic Networks and Pathways10aMice10aMice, Nude10aMicroarray Analysis10aMolecular Sequence Annotation10aPrincipal Component Analysis10aSignal Transduction10aSkin10aSkin Transplantation10aSkin Ulcer10aStreptozocin10aTissue Engineering10aTranscriptome10aTransplantation, Heterologous10aWound Healing1 aLeón, Carlos1 aGarcia-Garcia, Francisco1 aLlames, Sara1 aGarcía-Pérez, Eva1 aCarretero, Marta1 aArriba, María, Del Carmen1 aDopazo, Joaquin1 aDel Rio, Marcela1 aEscamez, Maria, José1 aMartínez-Santamaría, Lucía  uhttp://clinbioinfosspa.es/content/transcriptomic-analysis-diabetic-skin-humanized-mouse-model-dissects-molecular-pathways02121nas a2200289   4500008004100000022001400041245015000055210006900205260001500274300000700289490000700296520113800303653001501441653001101456653003101467653002101498653001501519653001501534653001701549653001501566100003301581700002001614700002701634700002601661700002001687856012401707       2019                        eng d  a1745-615000aAntibiotic resistance and metabolic profiles as functional biomarkers that accurately predict the geographic origin of city metagenomics samples.0 aAntibiotic resistance and metabolic profiles as functional bioma  c2019 08 20  a150 v143 a<p><b>BACKGROUND: </b>The availability of hundreds of city microbiome profiles allows the development of increasingly accurate predictors of the origin of a sample based on its microbiota composition. Typical microbiome studies involve the analysis of bacterial abundance profiles.</p><p><b>RESULTS: </b>Here we use a transformation of the conventional bacterial strain or gene abundance profiles to functional profiles that account for bacterial metabolism and other cell functionalities. These profiles are used as features for city classification in a machine learning algorithm that allows the extraction of the most relevant features for the classification.</p><p><b>CONCLUSIONS: </b>We demonstrate here that the use of functional profiles not only predict accurately the most likely origin of a sample but also to provide an interesting functional point of view of the biogeography of the microbiota. Interestingly, we show how cities can be classified based on the observed profile of antibiotic resistances.</p><p><b>REVIEWERS: </b>Open peer review: Reviewed by Jin Zhuang Dou, Jing Zhou, Torsten Semmler and Eran Elhaik.</p>10abiomarkers10aCities10aDrug Resistance, Microbial10aMachine Learning10aMetabolome10aMetagenome10ametagenomics10aMicrobiota1 aCasimiro-Soriguer, Carlos, S1 aLoucera, Carlos1 aFlorido, Javier, Perez1 aLópez-López, Daniel1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/antibiotic-resistance-and-metabolic-profiles-functional-biomarkers-accurately-predict01814nas a2200265   4500008004100000022001400041245007700055210006900132260001600201300001400217490000700231520098400238653001501222653001101237653002301248653002401271653002001295653001801315100001901333700002201352700001801374700003101392700002001423856010501443       2019                        eng d  a1477-405400aA comparison of mechanistic signaling pathway activity analysis methods.0 acomparison of mechanistic signaling pathway activity analysis me  c2019 Sep 27  a1655-16680 v203 a<p>Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.</p>10aAlgorithms10aHumans10aPostmortem Changes10aSignal Transduction10aSystems biology10aTranscriptome1 aAmadoz, Alicia1 aHidalgo, Marta, R1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/comparison-mechanistic-signaling-pathway-activity-analysis-methods02834nas a2200397   4500008004100000022001400041245011600055210006900171260000900240300000600249490000600255520157600261653002601837653002401863653001901887653002901906653001101935653001301946653003601959653002301995653001402018653001402032653001302046653001802059100001802077700002202095700001902117700001602136700002402152700002202176700002102198700002002219700003102239700002002270856014602290       2019                        eng d  a2056-718900aDifferential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.0 aDifferential metabolic activity and discovery of therapeutic tar  c2019  a70 v53 a<p>In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.</p>10aComputational Biology10aComputer Simulation10aDrug discovery10aGene Regulatory Networks10aHumans10aInternet10aMetabolic Networks and Pathways10aModels, Biological10aNeoplasms10aPhenotype10aSoftware10aTranscriptome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aRian, Kinza1 aSalavert, Francisco1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/differential-metabolic-activity-and-discovery-therapeutic-targets-using-summarized-metabolic-pathway-models01957nas a2200277   4500008004100000022001400041245011500055210006900170260001600239300000800255490000700263520105900270653002301329653001901352653001301371653001101384653002101395653001401416653001301430653002401443100002701467700002401494700002001518700002001538856012101558       2019                        eng d  a1471-210500aExploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models.0 aExploring the druggable space around the Fanconi anemia pathway   c2019 Jul 02  a3700 v203 a<p><b>BACKGROUND: </b>In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.</p><p><b>RESULTS: </b>The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.</p><p><b>CONCLUSIONS: </b>The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.</p>10aDatabases, Factual10aFanconi Anemia10aGenomics10aHumans10aMachine Learning10aPhenotype10aProteins10aSignal Transduction1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aLoucera, Carlos1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/exploring-druggable-space-around-fanconi-anemia-pathway-using-machine-learning-and05219nas a2200661   4500008004100000022001400041245013800055210006900193260001300262300001200275490000700287520316900294653001003463653000903473653002803482653002603510653001103536653001103547653001403558653000903572653001603581653002603597653001603623653004903639653002603688653002803714653001703742653002203759100002503781700002403806700002503830700002003855700002103875700002203896700002103918700002203939700002303961700002003984700002404004700002204028700002204050700001804072700001904090700003004109700002904139700002304168700001804191700002904209700002404238700001704262700001504279700002004294700002704314700001804341700002004359700001904379856015904398       2019                        eng d  a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat  c2019 Jan  a134-1440 v203 a<p><b>BACKGROUND: </b>A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.</p><p><b>METHODS: </b>In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.</p><p><b>FINDINGS: </b>From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).</p><p><b>INTERPRETATION: </b>To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.</p><p><b>FUNDING: </b>Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.</p>10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina  uhttp://clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour-multicentre-single-arm-phase-2-trial02190nas a2200241   4500008004100000022001400041245006800055210006700123260001600190300001200206490000700218520142700225653001901652653002601671653001101697653002301708100002701731700002001758700002201778700002201800700002501822856010101847       2019                        eng d  a1477-405400aPrecision medicine needs pioneering clinical bioinformaticians.0 aPrecision medicine needs pioneering clinical bioinformaticians  c2019 May 21  a752-7660 v203 a<p>Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of 'precision bioinformatics', and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.</p>10aCohort Studies10aComputational Biology10aHumans10aPrecision Medicine1 aGómez-López, Gonzalo1 aDopazo, Joaquin1 aCigudosa, Juan, C1 aValencia, Alfonso1 aAl-Shahrour, Fátima  uhttp://clinbioinfosspa.es/content/precision-medicine-needs-pioneering-clinical-bioinformaticians02565nas a2200253   4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520169900265653002601964653002301990653001302013653002802026100002202054700002402076700002002100700002402120700002002144700002002164856012702184       2019                        eng d  a1471-210500aPyCellBase, an efficient python package for easy retrieval of biological data from heterogeneous sources.0 aPyCellBase an efficient python package for easy retrieval of bio  c2019 Mar 28  a1590 v203 a<p><b>BACKGROUND: </b>Biological databases and repositories are incrementing in diversity and complexity over the years. This rapid expansion of current and new sources of biological knowledge raises serious problems of data accessibility and integration. To handle the growing necessity of unification, CellBase was created as an integrative solution. CellBase provides a centralized NoSQL database containing biological information from different and heterogeneous sources. Access to this information is done through a RESTful web service API, which provides an efficient interface to the data.</p><p><b>RESULTS: </b>In this work we present PyCellBase, a Python package that provides programmatic access to the rich RESTful web service API offered by CellBase. This package offers a fast and user-friendly access to biological information without the need of installing any local database. In addition, a series of command-line tools are provided to perform common bioinformatic tasks, such as variant annotation. CellBase data is always available by a high-availability cluster and queries have been tuned to ensure a real-time performance.</p><p><b>CONCLUSION: </b>PyCellBase is an open-source Python package that provides an efficient access to heterogeneous biological information. It allows to perform tasks that require a comprehensive set of knowledge resources, as for example variant annotation. Queries can be easily fine-tuned to retrieve the desired information of particular biological features. PyCellBase offers the convenience of an object-oriented scripting language and provides the ability to integrate the obtained results into other Python applications and pipelines.</p>10aComputational Biology10aDatabases, Factual10aSoftware10aUser-Computer Interface1 aPerez-Gil, Daniel1 aLopez, Francisco, J1 aDopazo, Joaquin1 aMarin-Garcia, Pablo1 aRendon, Augusto1 aMedina, Ignacio  uhttp://clinbioinfosspa.es/content/pycellbase-efficient-python-package-easy-retrieval-biological-data-heterogeneous-sources00765nas a2200181   4500008004100000245009000041210006900131260001600200490000600216100002400222700002700246700002200273700001600295700002300311700002000334700002000354856020900374       2019                        eng d00aUsing mechanistic models for the clinical interpretation of complex genomic variation0 aUsing mechanistic models for the clinical interpretation of comp  cJan-12-20190 v91 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aFalco, Matias, M.1 aRian, Kinza1 aHidalgo, Marta, R.1 aLoucera, Carlos1 aDopazo, Joaquin  uhttp://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-702573nas a2200529   4500008004100000022001400041245008700055210006900142260001600211300000800227490000600235520103000241653001001271653001801281653001001299653001101309653002001320653001101340653002301351653002301374653001901397653002501416653001801441100002301459700002701482700002101509700002501530700001601555700001901571700001701590700002201607700002401629700003101653700002101684700002401705700001901729700002401748700001801772700001801790700002101808700002001829700002001849700002101869700002301890700002001913856011001933       2018                        eng d  a2041-172300aThe effects of death and post-mortem cold ischemia on human tissue transcriptomes.0 aeffects of death and postmortem cold ischemia on human tissue tr  c2018 Feb 13  a4900 v93 a<p>Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.</p>10aBlood10aCold Ischemia10aDeath10aFemale10agene expression10aHumans10aModels, Biological10aPostmortem Changes10aRNA, Messenger10aStochastic Processes10aTranscriptome1 aFerreira, Pedro, G1 aMuñoz-Aguirre, Manuel1 aReverter, Ferran1 aGodinho, Caio, P Sá1 aSousa, Abel1 aAmadoz, Alicia1 aSodaei, Reza1 aHidalgo, Marta, R1 aPervouchine, Dmitri1 aCarbonell-Caballero, José1 aNurtdinov, Ramil1 aBreschi, Alessandra1 aAmador, Raziel1 aOliveira, Patrícia1 aCubuk, Cankut1 aCurado, João1 aAguet, François1 aOliveira, Carla1 aDopazo, Joaquin1 aSammeth, Michael1 aArdlie, Kristin, G1 aGuigó, Roderic  uhttp://clinbioinfosspa.es/content/effects-death-and-post-mortem-cold-ischemia-human-tissue-transcriptomes02783nas a2200349   4500008004100000022001400041245008700055210006900142260001300211490000600224520171300230653001201943653003001955653001101985653002201996653001302018653001102031653000902042653001002051653002702061100003302088700002902121700002002150700003002170700002102200700001902221700002002240700001902260700001902279700002202298856011302320       2018                        eng d  a2057-585800aThe first complete genomic structure of Butyrivibrio fibrisolvens and its chromid.0 afirst complete genomic structure of Butyrivibrio fibrisolvens an  c2018 Oct0 v43 a<p>Butyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.</p>10aAnimals10aButyrivibrio fibrisolvens10aCattle10aGenome, Bacterial10aGenomics10aHumans10aMilk10aRumen10aSequence Analysis, DNA1 aHernáez, Javier, Rodríguez1 aCucchi, Maria, Esperanza1 aCravero, Silvio1 aMartinez, Maria, Carolina1 aGonzalez, Sergio1 aPuebla, Andrea1 aDopazo, Joaquin1 aFarber, Marisa1 aPaniego, Norma1 aRivarola, Máximo  uhttp://clinbioinfosspa.es/content/first-complete-genomic-structure-butyrivibrio-fibrisolvens-and-its-chromid02946nas a2200445   4500008004100000022001400041245009500055210006900150260001600219300001400235490000700249520156700256653002101823653002101844653002401865653003001889653004301919653002901962653001101991653002602002653001502028653001302043653001402056653001402070653001402084653001402098653002702112653002702139653001802166653002202184100001802206700002202224700001902246700002202265700002102287700002002308700003102328700002002359856012102379       2018                        eng d  a1538-744500aGene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.0 aGene Expression Integration into Pathway Modules Reveals a PanCa  c2018 Nov 01  a6059-60720 v783 a<p>Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .</p>10aCell Line, Tumor10aCluster Analysis10aDisease Progression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Regulatory Networks10aHumans10aKaplan-Meier Estimate10aMetabolome10amutation10aNeoplasms10aOncogenes10aPhenotype10aPrognosis10aRNA, Small Interfering10aSequence Analysis, RNA10aTranscriptome10aTreatment Outcome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-expression-integration-pathway-modules-reveals-pan-cancer-metabolic-landscape02577nas a2200517   4500008004100000022001400041245005200055210005100107260001600158300001200174490000800186520112500194653002301319653001701342653001101359653002001370653002501390653002301415653001801438653001301456653001501469653001701484653002101501653002001522653002701542653001401569100002401583700001801607700002201625700002801647700002601675700002101701700002001722700002401742700003101766700002001797700001701817700001801834700002401852700002101876700002001897700002601917700002301943700001801966856007501984       2018                        eng d  a1476-468700aGenomics of the origin and evolution of Citrus.0 aGenomics of the origin and evolution of Citrus  c2018 Feb 15  a311-3160 v5543 a<p>The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus.</p>10aAsia, Southeastern10aBiodiversity10acitrus10aCrop Production10aEvolution, Molecular10aGenetic Speciation10aGenome, Plant10aGenomics10aHaplotypes10aHeterozygote10aHistory, Ancient10aHuman Migration10aHybridization, Genetic10aPhylogeny1 aWu, Guohong, Albert1 aTerol, Javier1 aIbañez, Victoria1 aLópez-García, Antonio1 aPérez-Román, Estela1 aBorredá, Carles1 aDomingo, Concha1 aTadeo, Francisco, R1 aCarbonell-Caballero, José1 aAlonso, Roberto1 aCurk, Franck1 aDu, Dongliang1 aOllitrault, Patrick1 aRoose, Mikeal, L1 aDopazo, Joaquin1 aGmitter, Frederick, G1 aRokhsar, Daniel, S1 aTalon, Manuel  uhttp://clinbioinfosspa.es/content/genomics-origin-and-evolution-citrus02251nas a2200277   4500008004100000022001400041245011400055210006900169260001600238300000700254490000700261520126600268653002601534653004301560653001101603653004201614653002401656653001801680653002401698100002201722700001901744700001801763700003101781700002001812856014101832       2018                        eng d  a1745-615000aModels of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.0 aModels of cell signaling uncover molecular mechanisms of highris  c2018 Aug 22  a160 v133 a<p><b>BACKGROUND: </b>Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.</p><p><b>RESULTS: </b>Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.</p><p><b>CONCLUSION: </b>We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.</p><p><b>REVIEWERS: </b>This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.</p>10aComputational Biology10aGene Expression Regulation, Neoplastic10aHumans10aJNK Mitogen-Activated Protein Kinases10aModels, Theoretical10aNeuroblastoma10aSignal Transduction1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/models-cell-signaling-uncover-molecular-mechanisms-high-risk-neuroblastoma-and-predict-disease-outcome02943nas a2200541   4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653002101661653001101682653002901693653003201722653002601754653001101780653001401791653002901805653000901834653001601843653001301859653002201872653001801894653001401912100002101926700003101947700002001978700002401998700002402022700002602046700001602072700001902088700001902107700002502126700002002151700001902171700002002190700002002210700002402230700002002254700001902274856010802293       2018                        eng d  a1932-620300aThe modular network structure of the mutational landscape of Acute Myeloid Leukemia.0 amodular network structure of the mutational landscape of Acute M  c2018  ae02029260 v133 a<p>Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.</p>10aAdult10aAged10aCytodiagnosis10aExome Sequencing10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aSuch, Esperanza1 aGarcía-Alonso, Luz1 aLiquori, Alessandro1 aLópez-Pavía, María1 aLLop, Marta1 aAlonso, Carmen1 aBarragán, Eva1 aGómez-Seguí, Inés1 aNeef, Alexander1 aHervás, David1 aMontesinos, Pau1 aSanz, Guillermo1 aSanz, Miguel, Angel1 aDopazo, Joaquin1 aCervera, José  uhttp://clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia02395nas a2200313   4500008004100000022001400041245011300055210006900168260001600237300000800253490000700261520133500268653001201603653002301615653003001638653004201668653001301710653002701723653001801750653002801768100002101796700002201817700002201839700002101861700002101882700002001903700001901923856013901942       2017                        eng d  a1471-210500aATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data.0 aATGC transcriptomics a webbased application to integrate explore  c2017 Feb 22  a1210 v183 a<p><b>BACKGROUND: </b>In the last years, applications based on massively parallelized RNA sequencing (RNA-seq) have become valuable approaches for studying non-model species, e.g., without a fully sequenced genome. RNA-seq is a useful tool for detecting novel transcripts and genetic variations and for evaluating differential gene expression by digital measurements. The large and complex datasets resulting from functional genomic experiments represent a challenge in data processing, management, and analysis. This problem is especially significant for small research groups working with non-model species.</p><p><b>RESULTS: </b>We developed a web-based application, called ATGC transcriptomics, with a flexible and adaptable interface that allows users to work with new generation sequencing (NGS) transcriptomic analysis results using an ontology-driven database. This new application simplifies data exploration, visualization, and integration for a better comprehension of the results.</p><p><b>CONCLUSIONS: </b>ATGC transcriptomics provides access to non-expert computer users and small research groups to a scalable storage option and simple data integration, including database administration and management. The software is freely available under the terms of GNU public license at http://atgcinta.sourceforge.net .</p>10aAnimals10aDatabases, Genetic10aGene Expression Profiling10aHigh-Throughput Nucleotide Sequencing10aInternet10aSequence Analysis, RNA10aTranscriptome10aUser-Computer Interface1 aGonzalez, Sergio1 aClavijo, Bernardo1 aRivarola, Máximo1 aMoreno, Patricio1 aFernandez, Paula1 aDopazo, Joaquin1 aPaniego, Norma  uhttp://clinbioinfosspa.es/content/atgc-transcriptomics-web-based-application-integrate-explore-and-analyze-de-novo-transcriptomic-data02800nas a2200445   4500008004100000022001400041245015700055210006900212260001600281300001600297490000600313520134500319653001001664653002501674653002601699653002001725653003801745653001301783653001501796653001101811653001801822653001601840653001601856653001401872653003501886100003001921700002401951700002201975700002601997700002902023700002202052700002602074700002502100700002402125700002102149700002002170700001802190700001702208856012902225       2017                        eng d  a1949-255300aGenomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.0 aGenomic expression differences between cutaneous cells from red   c2017 Feb 14  a11589-115990 v83 a<p>The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.</p>10aAdult10aCoculture Techniques10aComputational Biology10agene expression10aGenetic Predisposition to Disease10aGenomics10aHair Color10aHumans10aKeratinocytes10aMelanocytes10aMiddle Aged10aPhenotype10aReceptor, Melanocortin, Type 11 aPuig-Butille, Joan, Anton1 aGimenez-Xavier, Pol1 aVisconti, Alessia1 aNsengimana, Jérémie1 aGarcia-Garcia, Francisco1 aTell-Marti, Gemma1 aEscamez, Maria, José1 aNewton-Bishop, Julia1 aBataille, Veronique1 aDel Rio, Marcela1 aDopazo, Joaquin1 aFalchi, Mario1 aPuig, Susana  uhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14140&path%5B%5D=4509401431nas a2200481   4500008004100000022001400041245007200055210006900127260001600196300001400212490000800226653000900234653002400243653003700267653003400304653001900338653001000357653002900367653001100396653002200407653002800429653001100457653001600468653001300484100002100497700002100518700002800539700002700567700002600594700002000620700002000640700002000660700002900680700002000709700002600729700002800755700002200783700002400805700002000829700002100849700002500870856005400895       2017                        eng d  a1533-440600aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.0 aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonat  c2017 May 04  a1794-17950 v37610aAged10aAmino Acid Sequence10aBone Density Conservation Agents10aDimethylallyltranstransferase10aDiphosphonates10aExome10aFarnesyltranstransferase10aFemale10aFemoral Fractures10aGeranyltranstransferase10aHumans10aMiddle Aged10amutation1 aRoca-Ayats, Neus1 aBalcells, Susana1 aGarcia-Giralt, Natàlia1 aFalcó-Mascaró, Maite1 aMartínez-Gil, Núria1 aAbril, Josep, F1 aUrreizti, Roser1 aDopazo, Joaquin1 aQuesada-Gómez, José, M1 aNogués, Xavier1 aMellibovsky, Leonardo1 aPrieto-Alhambra, Daniel1 aDunford, James, E1 aJavaid, Muhammad, K1 aRussell, Graham1 aGrinberg, Daniel1 aDíez-Pérez, Adolfo  uhttp://www.nejm.org/doi/full/10.1056/NEJMc161280402580nas a2200349   4500008004100000022001400041245014600055210006900201260001500270300001200285490000700297520142200304653001201726653001501738653002001753653002001773653003501793653003001828653002101858653002401879653002301903653001201926653001601938653001801954653002101972100002301993700002902016700002002045700001702065700001902082856012902101       2017                        eng d  a1460-219900aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types.0 aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells I  c2017 01 01  a706-7170 v273 a<p>Thyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3-treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development.</p>10aAnimals10aAstrocytes10aCells, Cultured10aCerebral Cortex10aFluorescent Antibody Technique10aGene Expression Profiling10aMice, 129 Strain10aMice, Inbred BALB C10aMice, Inbred C57BL10aNeurons10aPiperazines10aTranscriptome10aTriiodothyronine1 aGil-Ibañez, Pilar1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aBernal, Juan1 aMorte, Beatriz  uhttp://clinbioinfosspa.es/content/global-transcriptome-analysis-primary-cerebrocortical-cells-identification-genes-regulated03363nas a2200241   4500008004100000022001400041245008900055210006900144260001600213300000800229490000700237520258700244653002102831653001102852653002902863653002802892653001102920653002402931653001302955100002002968700001702988856011603005       2017                        eng d  a1752-050900aGraph-theoretical comparison of normal and tumor networks in identifying BRCA genes.0 aGraphtheoretical comparison of normal and tumor networks in iden  c2017 Nov 22  a1100 v113 a<p><b>BACKGROUND: </b>Identification of driver genes related to certain types of cancer is an important research topic. Several systems biology approaches have been suggested, in particular for the identification of breast cancer (BRCA) related genes. Such approaches usually rely on differential gene expression and/or mutational landscape data. In some cases interaction network data is also integrated to identify cancer-related modules computationally.</p><p><b>RESULTS: </b>We provide a framework for the comparative graph-theoretical analysis of networks integrating the relevant gene expression, mutations, and potein-protein interaction network data. The comparisons involve a graph-theoretical analysis of normal and tumor network pairs across all instances of a given set of breast cancer samples. The network measures under consideration are based on appropriate formulations of various centrality measures: betweenness, clustering coefficients, degree centrality, random walk distances, graph-theoretical distances, and Jaccard index centrality.</p><p><b>CONCLUSIONS: </b>Among all the studied centrality-based graph-theoretical properties, we show that a betweenness-based measure differentiates BRCA genes across all normal versus tumor network pairs, than the rest of the popular centrality-based measures. The AUROC and AUPR values of the gene lists ordered with respect to the measures under study as compared to NCBI BioSystems pathway and the COSMIC database of cancer genes are the largest with the betweenness-based differentiation, followed by the measure based on degree centrality. In order to test the robustness of the suggested measures in prioritizing cancer genes, we further tested the two most promising measures, those based on betweenness and degree centralities, on randomly rewired networks. We show that both measures are quite resilient to noise in the input interaction network. We also compared the same measures against a state-of-the-art alternative disease gene prioritization method, MUFFFINN. We show that both our graph-theoretical measures outperform MUFFINN prioritizations in terms of ROC and precions/recall analysis. Finally, we filter the ordered list of the best measure, the betweenness-based differentiation, via a maximum-weight independent set formulation and investigate the top 50 genes in regards to literature verification. We show that almost all genes in the list are verified by the breast cancer literature and three genes are presented as novel genes that may potentialy be BRCA-related but missing in literature.</p>10aBreast Neoplasms10aFemale10aGene Regulatory Networks10aGenes, Tumor Suppressor10aHumans10aModels, Theoretical10amutation1 aDopazo, Joaquin1 aErten, Cesim  uhttp://clinbioinfosspa.es/content/graph-theoretical-comparison-normal-and-tumor-networks-identifying-brca-genes00523nas a2200121   4500008004100000245008800041210006900129260001600198490000700214100002000221700001700241856014300258       2017                        eng d00aGraph-theoretical comparison of normal and tumor networks in identifying BRCA genes0 aGraphtheoretical comparison of normal and tumor networks in iden  cJan-12-20170 v111 aDopazo, Joaquin1 aErten, Cesim  uhttps://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-017-0495-0http://link.springer.com/content/pdf/10.1186/s12918-017-0495-0.pdf02299nas a2200361   4500008004100000022001400041245004600055210004400101260001600145300001400161490000700175520132500182653002201507653001801529653001101547653001301558653001301571653002801584100001801612700001701630700002101647700002301668700002301691700002201714700001601736700001701752700001901769700001801788700002001806700002001826700002001846856007101866       2017                        eng d  a1362-496200aHGVA: the Human Genome Variation Archive.0 aHGVA the Human Genome Variation Archive  c2017 Jul 03  aW189-W1940 v453 a<p>High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.</p>10aGenetic Variation10aGenome, Human10aHumans10aInternet10aSoftware10aUser-Computer Interface1 aLopez, Javier1 aColl, Jacobo1 aHaimel, Matthias1 aKandasamy, Swaathi1 aTárraga, Joaquín1 aFurio-Tari, Pedro1 aBari, Wasim1 aBleda, Marta1 aRueda, Antonio1 aGräf, Stefan1 aRendon, Augusto1 aDopazo, Joaquin1 aMedina, Ignacio  uhttps://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx44502079nas a2200313   4500008004100000022001400041245012900055210006900184260001600253300001400269490000600283520099600289653002601285653002001311653002901331653001101360653001301371653001401384653002301398653002701421653002401448100002201472700001801494700001901512700002401531700003101555700002001586856015901606       2017                        eng d  a1949-255300aHigh throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.0 aHigh throughput estimation of functional cell activities reveals  c2017 Jan 17  a5160-51780 v83 a<p>Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.</p>10aComputational Biology10agene expression10aGene Regulatory Networks10aHumans10amutation10aNeoplasms10aPrecision Medicine10aSequence Analysis, RNA10aSignal Transduction1 aHidalgo, Marta, R1 aCubuk, Cankut1 aAmadoz, Alicia1 aSalavert, Francisco1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/high-throughput-estimation-functional-cell-activities-reveals-disease-mechanisms-and-predicts-relevant-clinical-outcomes03062nas a2200433   4500008004100000022001400041245016000055210006900215260001300284300001200297490000700309520160000316653001601916653003801932653001501970653001701985653001902002653002702021653001502048653002602063653002602089653001002115100002402125700002402149700001902173700002002192700002202212700002102234700002202255700002902277700002002306700001802326700002002344700002402364700001902388700002102407700001902428856018102447       2017                        eng d  a1573-502800aIntegration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.).0 aIntegration of transcriptomic and metabolic data reveals hub tra  c2017 Jul  a549-5640 v943 a<p>By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.</p>10aChlorophyll10aGene Expression Regulation, Plant10aHelianthus10aPlant Leaves10aPlant Proteins10aProtein Array Analysis10aRNA, Plant10aStress, Physiological10aTranscription Factors10aWater1 aMoschen, Sebastián1 aDi Rienzo, Julio, A1 aHiggins, Janet1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A  uhttp://clinbioinfosspa.es/content/integration-transcriptomic-and-metabolic-data-reveals-hub-transcription-factors-involved-drought-stress-response-sunflower-helianthus-annuus-l02561nas a2200541   4500008004100000022001400041245008600055210006900141260001300210300001200223490000700235520094000242653002801182653001201210653002801222653001001250653004201260653001301302653001101315653003101326653000901357653001301366653001401379653003301393653002801426100002201454700001701476700002501493700003201518700002201550700001801572700002101590700002001611700002401631700003401655700001901689700002001708700002901728700002501757700001901782700002001801700001901821700001801840700001701858700001901875700001901894856010601913       2017                        eng d  a1098-100400aMutations in TRAPPC11 are associated with a congenital disorder of glycosylation.0 aMutations in TRAPPC11 are associated with a congenital disorder   c2017 Feb  a148-1510 v383 a<p>Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.</p>10aAbnormalities, Multiple10aAlleles10aAmino Acid Substitution10aBrain10aCongenital Disorders of Glycosylation10aGenotype10aHumans10aMagnetic Resonance Imaging10aMale10amutation10aPhenotype10aVesicular Transport Proteins10aWhole Genome Sequencing1 aMatalonga, Leslie1 aBravo, Miren1 aSerra-Peinado, Carla1 aGarcía-Pelegrí, Elisabeth1 aUgarteburu, Olatz1 aVidal, Silvia1 aLlambrich, Maria1 aQuintana, Ester1 aFuster-Jorge, Pedro1 aGonzalez-Bravo, Maria, Nieves1 aBeltran, Sergi1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aFoulquier, François1 aMatthijs, Gert1 aMills, Philippa1 aRibes, Antonia1 aEgea, Gustavo1 aBriones, Paz1 aTort, Frederic1 aGirós, Marisa  uhttp://clinbioinfosspa.es/content/mutations-trappc11-are-associated-congenital-disorder-glycosylation02685nas a2200349   4500008004100000022001400041245011500055210006900170260001600239300001400255490000700269520162000276653001201896653002201908653001101930653001301941653001301954653001101967653002401978653002002002653003102022653001302053100003102066700001902097700002002116700002202136700001802158700001802176700002802194700002002222856009302242       2017                        eng d  a1367-481100aReference genome assessment from a population scale perspective: an accurate profile of variability and noise.0 aReference genome assessment from a population scale perspective   c2017 Nov 15  a3511-35170 v333 a<p><b>MOTIVATION: </b>Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.</p><p><b>RESULTS: </b>The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>This tool is freely available at http://gitlab.com/carbonell/ces.</p><p><b>CONTACT: </b>jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.</p><p><b>SUPPLEMENTARY INFORMATION: </b>Supplementary data are available at Bioinformatics online.</p>10aAnimals10aGenetic Variation10aGenome10aGenomics10aGenotype10aHumans10aModels, Statistical10aQuality Control10aReproducibility of Results10aSoftware1 aCarbonell-Caballero, José1 aAmadoz, Alicia1 aAlonso, Roberto1 aHidalgo, Marta, R1 aCubuk, Cankut1 aConesa, David1 aLópez-Quílez, Antonio1 aDopazo, Joaquin  uhttps://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx48201955nas a2200325   4500008004100000022001400041245009200055210006900147260001600216300000800232490000700240520091900247653001801166653002001184653002001204653004201224653001101266653001301277653002801290653002201318100002101340700002301361700002301384700002201407700002401429700002001453700001901473700002001492856011701512       2017                        eng d  a1471-210500aVISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.0 aVISMapper ultrafast exhaustive cartography of viral insertion si  c2017 Sep 20  a4210 v183 a<p><b>BACKGROUND: </b>The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.</p><p><b>RESULTS: </b>Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .</p><p><b>CONCLUSIONS: </b>Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.</p>10aBase Sequence10aGenetic Therapy10aGenetic Vectors10aHigh-Throughput Nucleotide Sequencing10aHumans10aInternet10aUser-Computer Interface10aVirus Integration1 aJuanes, José, M1 aGallego, Asunción1 aTárraga, Joaquín1 aChaves, Felipe, J1 aMarin-Garcia, Pablo1 aMedina, Ignacio1 aArnau, Vicente1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/vismapper-ultra-fast-exhaustive-cartography-viral-insertion-sites-gene-therapy03542nas a2200649   4500008004100000022001400041245010900055210006900164260001600233300000700249490000700256520162800263653001601891653001701907653000801924100001901932700002001951700002201971700002501993700002502018700002202043700001702065700002102082700002502103700001902128700002202147700002002169700002102189700001902210700001802229700001802247700002202265700002302287700001802310700002002328700001602348700002602364700001702390700002202407700001702429700002202446700002102468700003202489700002802521700002302549700002902572700002502601700001802626700001902644700002502663700002602688700002302714700001902737700003402756700002402790856007802814       2017                        eng d  a1474-760X00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.0 aWhole exome sequencing coupled with unbiased functional analysis  c2017 Mar 08  a480 v183 aBACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.10aHirschprung10aRare Disease10aWES1 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W1 aChauhan, Rajendra, K1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S1 aBrouwer, Rutger, W W1 aBurns, Alan, J1 aCherny, Stacey, S1 aDopazo, Joaquin1 aEggen, Bart, J L1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C H1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S W1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C1 aShepherd, Iain, T1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S M1 avan den Hout, Mirjam, C G N1 avan der Linde, Herma, C1 avan Ham, Tjakko, J1 avan IJcken, Wilfred, F J1 aVerheij, Joke, B G M1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K H1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, Mw  uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-601877nas a2200577   4500008004100000245010800041210006900149260001600218490000700234100001900241700002000260700002300280700002600303700002500329700002200354700001700376700002200393700002700415700002000442700002300462700002000485700002300505700001900528700001800547700001800565700002400583700002300607700001800630700002200648700001600670700002600686700001800712700002300730700001700753700002200770700002300792700003500815700002900850700002400879700003100903700002800934700001800962700001900980700002500999700002601024700002301050700002101073700003401094700002701128856014401155       2017                        eng d00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes0 aWhole exome sequencing coupled with unbiased functional analysis  cJan-12-20170 v181 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W.1 aChauhan, Rajendra, K.1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S.1 aBrouwer, Rutger, W. W.1 aBurns, Alan, J.1 aCherny, Stacey, S.1 aDopazo, Joaquin1 aEggen, Bart, J. L.1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C. H.1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S. W.1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C.1 aShepherd, Iain, T.1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S. M.1 avan den Hout, Mirjam, C. G. N.1 avan der Linde, Herma, C.1 avan Ham, Tjakko, J.1 avan IJcken, Wilfred, F. J.1 aVerheij, Joke, B. G. M.1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K. H.1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, M. W.  uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf02634nas a2200289   4500008004100000022001400041245015800055210006900213260001500282300000900297520167800306653001901984653001202003653000902015653000902024653002302033653001202056653002102068100002302089700001802112700003002130700002302160700002002183700002402203700002902227856008802256       2016                        eng d  a1607-888800aChronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.0 aChronic subordination stress selectively downregulates the insul  c2016 Mar 7  a1-113 aChronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.10aAdipose tissue10ainsulin10aIRS110aIRS210ametabolic syndrome10aobesity10apathway analysis1 aSanghez, Valentina1 aCubuk, Cankut1 aSebastián-Leon, Patricia1 aCarobbio, Stefania1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aBartolomucci, Alessandro  uhttp://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists2002237nas a2200409   4500008004100000022001400041245006800055210006700123260001300190300001400203490000700217520102100224653001201245653002701257653002701284653001501311653001301326653003001339653000901369653002701378653001201405653002601417653002701443653002601470100001901496700001801515700002001533700002901553700001601582700001501598700002701613700002001640700002001660700002701680700001901707856010101726       2016                        eng d  a1551-400500aDysfunctional mitochondrial fission impairs cell reprogramming.0 aDysfunctional mitochondrial fission impairs cell reprogramming  c2016 Dec  a3240-32500 v153 a<p>We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.</p>10aAnimals10aCell Cycle Checkpoints10aCellular Reprogramming10aDNA Damage10aG2 Phase10aGene Knockdown Techniques10aMice10aMitochondrial Dynamics10aMitosis10aNerve Tissue Proteins10aPluripotent Stem Cells10aTranscription Factors1 aPrieto, Javier1 aLeón, Marian1 aPonsoda, Xavier1 aGarcia-Garcia, Francisco1 aBort, Roque1 aSerna, Eva1 aBarneo-Muñoz, Manuela1 aPalau, Francesc1 aDopazo, Joaquin1 aLópez-García, Carlos1 aTorres, Josema  uhttp://clinbioinfosspa.es/content/dysfunctional-mitochondrial-fission-impairs-cell-reprogramming02094nas a2200349   4500008004100000022001400041245011200055210006900167260000900236300001000245490000600255520101800261100002001279700003401299700002701333700002701360700002201387700002301409700002401432700002101456700001901477700002001496700002301516700002201539700001901561700003301580700002001613700002301633700002001656700002101676856004701697       2016                        eng d  a2041-172300aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq).0 aExtension of human lncRNA transcripts by RACE coupled with longr  c2016  a123390 v73 aLong non-coding RNAs (lncRNAs) constitute a large, yet mostly uncharacterized fraction of the mammalian transcriptome. Such characterization requires a comprehensive, high-quality annotation of their gene structure and boundaries, which is currently lacking. Here we describe RACE-Seq, an experimental workflow designed to address this based on RACE (rapid amplification of cDNA ends) and long-read RNA sequencing. We apply RACE-Seq to 398 human lncRNA genes in seven tissues, leading to the discovery of 2,556 on-target, novel transcripts. About 60% of the targeted loci are extended in either 5’ or 3’, often reaching genomic hallmarks of gene boundaries. Analysis of the novel transcripts suggests that lncRNAs are as long, have as many exons and undergo as much alternative splicing as protein-coding genes, contrary to current assumptions. Overall, we show that RACE-Seq is an effective tool to annotate an organism’s deep transcriptome, and compares favourably to other targeted sequencing techniques.1 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M1 aSteward, Charles, A1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLópez-Domingo, Francisco, J1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer  uhttp://www.nature.com/articles/ncomms1233901158nas a2200313   4500008004100000245011100041210006900152260001600221490000600237100002000243700003400263700002700297700002700324700002200351700002400373700002500397700002100422700001900443700002000462700002300482700002200505700001900527700003300546700002000579700002300599700002000622700002100642856018100663       2016                        eng d00aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq)0 aExtension of human lncRNA transcripts by RACE coupled with longr  cJan-11-20160 v71 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M.1 aSteward, Charles, A.1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLopez-Domingo, Francisco, J.1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer  uhttp://www.nature.com/articles/ncomms12339http://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms1233901901nas a2200241   4500008004100000022001400041245008000055210006900135260000900204300000800213490000700221520123600228653001101464653000801475653001301483653000801496100002301504700002301527700001901550700002001569700002001589856005001609       2016                        eng d  a1471-210500aHPG pore: an efficient and scalable framework for nanopore sequencing data.0 aHPG pore an efficient and scalable framework for nanopore sequen  c2016  a1070 v173 aBACKGROUND: The use of nanopore technologies is expected to spread in the future because they are portable and can sequence long fragments of DNA molecules without prior amplification. The first nanopore sequencer available, the MinION™ from Oxford Nanopore Technologies, is a USB-connected, portable device that allows real-time DNA analysis. In addition, other new instruments are expected to be released soon, which promise to outperform the current short-read technologies in terms of throughput. Despite the flood of data expected from this technology, the data analysis solutions currently available are only designed to manage small projects and are not scalable. RESULTS: Here we present HPG Pore, a toolkit for exploring and analysing nanopore sequencing data. HPG Pore can run on both individual computers and in the Hadoop distributed computing framework, which allows easy scale-up to manage the large amounts of data expected to result from extensive use of nanopore technologies in the future. CONCLUSIONS: HPG Pore allows for virtually unlimited sequencing data scalability, thus guaranteeing its continued management in near future scenarios. HPG Pore is available in GitHub at http://github.com/opencb/hpg-pore .10ahadoop10aHPC10ananopore10aNGS1 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://www.biomedcentral.com/1471-2105/17/10700587nas a2200157   4500008004100000245007900041210006900120260001600189490000700205100002300212700002300235700001900258700002000277700002000297856011200317       2016                        eng d00aHPG pore: an efficient and scalable framework for nanopore sequencing data0 aHPG pore an efficient and scalable framework for nanopore sequen  cJan-12-20160 v171 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://www.biomedcentral.com/1471-2105/17/107http://link.springer.com/content/pdf/10.1186/s12859-016-0966-002756nas a2200397   4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520143100278653001201709653002401721653003101745653002801776653001701804653001701821653003201838653002601870653002001896653004201916653001101958653001301969653001401982653002401996100002302020700002802043700002502071700003302096700003602129700002002165700001902185700002502204856012902229       2016                        eng d  a2045-232200aImproving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.0 aImproving the management of Inherited Retinal Dystrophies by tar  c2016 Apr 01  a239100 v63 a<p>Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management. </p>10aAlleles10aComputer Simulation10aDNA Copy Number Variations10aDNA Mutational Analysis10aEye Proteins10aGene Library10aGenetic Association Studies10aGenetic Heterogeneity10aGenetic Therapy10aHigh-Throughput Nucleotide Sequencing10aHumans10amutation10aPhenotype10aRetinal Dystrophies1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aRomero-Pérez, Laura1 adel Pozo, María, González-1 ade la Rúa, Enrique, Rodríguez1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/improving-management-inherited-retinal-dystrophies-targeted-sequencing-population-specific02430nas a2200289   4500008004100000022001400041245005500055210005400110260001600164300001200180490000700192520155100199653002601750653003001776653001801806653002901824653004201853653001101895653001401906653001401920653003101934100002901965700002201994700002002016700002002036856008402056       2016                        eng d  a1367-481100aIntegrated gene set analysis for microRNA studies.0 aIntegrated gene set analysis for microRNA studies  c2016 Sep 15  a2809-160 v323 a<p><b>MOTIVATION: </b>Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.</p><p><b>RESULTS: </b>We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna</p><p><b>CONTACT: </b>: david.montaner@gmail.com</p><p><b>SUPPLEMENTARY INFORMATION: </b>Supplementary data are available at Bioinformatics online.</p>10aComputational Biology10aGene Expression Profiling10aGene ontology10aGene Regulatory Networks10aHigh-Throughput Nucleotide Sequencing10aHumans10aMicroRNAs10aNeoplasms10aReproducibility of Results1 aGarcia-Garcia, Francisco1 aPanadero, Joaquin1 aDopazo, Joaquin1 aMontaner, David  uhttp://clinbioinfosspa.es/content/integrated-gene-set-analysis-microrna-studies03249nas a2200493   4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520165600263653004101919653003001960653003801990653001802028653001702046653001502063653000902078653001702087653004402104653001702148653003302165653001902198653002602217100002402243700002602267700002402293700002802317700002002345700002202365700002102387700002102408700002202429700002902451700002002480700002702500700002002527700002402547700001902571700002102590700001902611856012502630       2016                        eng d  a1467-765200aIntegrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower.0 aIntegrating transcriptomic and metabolomic analysis to understan  c2016 Feb  a719-340 v143 a<p>Leaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up-regulated. Members of the NAC, AP2-EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process. </p>10aGas Chromatography-Mass Spectrometry10aGene Expression Profiling10aGene Expression Regulation, Plant10aGene ontology10aGenes, Plant10aHelianthus10aIons10ametabolomics10aOligonucleotide Array Sequence Analysis10aPlant Leaves10aPrincipal Component Analysis10aRNA, Messenger10aTranscription Factors1 aMoschen, Sebastián1 aLuoni, Sofía, Bengoa1 aDi Rienzo, Julio, A1 aCaro, María, Del Pilar1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aHollmann, Julien1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Horacio, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A  uhttp://clinbioinfosspa.es/content/integrating-transcriptomic-and-metabolomic-analysis-understand-natural-leaf-senescence02859nas a2200433   4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520145800288653001001746653002901756653001801785653001101803653001901814653003501833653001301868653001801881653003601899653003101935100002101966700003101987700002402018700002002042700002902062700001902091700001902110700002602129700001602155700001902171700002502190700002002215700002002235700002002255700001902275856013102294       2016                        eng d  a1932-620300aThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.0 aMutational Landscape of Acute Promyelocytic Leukemia Reveals an   c2016  ae01483460 v113 a<p>Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. </p>10aExome10aGene Regulatory Networks10aGenome, Human10aHumans10aINDEL Mutation10aLeukemia, Promyelocytic, Acute10amutation10aMutation Rate10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aGarcía-Alonso, Luz1 aSuch, Esperanza1 aJiménez-Almazán, Jorge1 aVidal, Enrique1 aBarragán, Eva1 aLópez-Pavía, María1 aLLop, Marta1 aMartín, Iván1 aGómez-Seguí, Inés1 aMontesinos, Pau1 aSanz, Miguel, A1 aDopazo, Joaquin1 aCervera, José  uhttp://clinbioinfosspa.es/content/mutational-landscape-acute-promyelocytic-leukemia-reveals-interacting-network-co-occurrences03502nas a2200517   4500008004100000022001400041245007400055210006900129260001300198300001000211490000800221520209300229653001002322653000902332653001202341653001002353653003202363653001102395653002002406653001102426653001102437653000902448653000902457653001602466653001302482653001302495653001402508653001802522653001602540653002602556653001602582100002002598700001902618700002902637700001802666700001902684700002502703700002402728700003102752700001802783700002002801700002202821700002002843700002102863856010002884       2016                        eng d  a1460-215600aMutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.0 aMutations in the MORC2 gene cause axonal CharcotMarieTooth disea  c2016 Jan  a62-720 v1393 a<p>Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease. </p>10aAdult10aAged10aAnimals10aAxons10aCharcot-Marie-Tooth Disease10aFemale10agene expression10aHumans10aInfant10aMale10aMice10aMiddle Aged10amutation10aPedigree10aPhenotype10aSciatic Nerve10aSural Nerve10aTranscription Factors10aYoung Adult1 aSevilla, Teresa1 aLupo, Vincenzo1 aMartínez-Rubio, Dolores1 aSancho, Paula1 aSivera, Rafael1 aChumillas, María, J1 aGarcía-Romero, Mar1 aPascual-Pascual, Samuel, I1 aMuelas, Nuria1 aDopazo, Joaquin1 aVílchez, Juan, J1 aPalau, Francesc1 aEspinós, Carmen  uhttp://clinbioinfosspa.es/content/mutations-morc2-gene-cause-axonal-charcot-marie-tooth-disease00573nas a2200145   4500008004100000245005300041210004800094260001600142490000600158100002200164700001700186700003100203700002000234856017300254       2016                        eng d00aThe pan-cancer pathological regulatory landscape0 apancancer pathological regulatory landscape  cJan-12-20160 v61 aFalco, Matias, M.1 aBleda, Marta1 aCarbonell-Caballero, José1 aDopazo, Joaquin  uhttp://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep3970902421nas a2200325   4500008004100000022001400041245006600055210006400121260001300185300001000198490000700208520140200215653002501617653003401642653003701676653001101713653002201724653002101746653003601767653002301803100002101826700001701847700002001864700002201884700003201906700001901938700002201957700002101979856009502000       2016                        eng d  a2363-891500aProgress in pharmacogenetics: consortiums and new strategies.0 aProgress in pharmacogenetics consortiums and new strategies  c2016 Mar  a17-230 v313 a<p>Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach. </p>10aCooperative Behavior10aGenome-Wide Association Study10aHigh-Throughput Screening Assays10aHumans10aPatient Care Team10apharmacogenetics10aPolymorphism, Single Nucleotide10aPrecision Medicine1 aMaroñas, Olalla1 aLatorre, Ana1 aDopazo, Joaquin1 aPirmohamed, Munir1 aRodríguez-Antona, Cristina1 aSiest, Gérard1 aCarracedo, Ángel1 aLLerena, Adrián  uhttp://clinbioinfosspa.es/content/progress-pharmacogenetics-consortiums-and-new-strategies02956nas a2200505   4500008004100000022001400041245008800055210006900143260001300212300001000225490000900235520151700244653001501761653001701776653001001793653002101803653002101824653001001845653001101855653004201866653001101908653001101919653002801930653000901958653001301967653001301980653001401993653001402007653002302021100002002044700002102064700001902085700002902104700002302133700002202156700002202178700001902200700001902219700002002238700001702258700002302275700002102298700002102319856011002340       2016                        eng d  a1552-483300aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.0 aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohri  c2016 Jan  a24-310 v170A3 a<p>Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.</p>10aAdolescent10aAntigens, CD10aChild10aChild, Preschool10aCraniosynostoses10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aIntellectual Disability10aMale10amutation10aPedigree10aPhenotype10aPrognosis10aRepressor Proteins1 aUrreizti, Roser1 aRoca-Ayats, Neus1 aTrepat, Judith1 aGarcia-Garcia, Francisco1 aAlemán, Alejandro1 aOrteschi, Daniela1 aMarangi, Giuseppe1 aNeri, Giovanni1 aOpitz, John, M1 aDopazo, Joaquin1 aCormand, Bru1 aVilageliu, Lluïsa1 aBalcells, Susana1 aGrinberg, Daniel  uhttp://clinbioinfosspa.es/content/screening-cd96-and-asxl1-11-patients-opitz-c-or-bohring-opitz-syndromes02605nas a2200397   4500008004100000022001400041245017300055210006900228260001600297300001300313490000600326520129300332653001001625653000901635653002201644653003501666653002401701653001101725653001101736653001901747653000901766653001701775653001601792653004301808100003001851700002801881700002501909700002901934700001501963700002101978700001601999700002002015700001802035700002702053856012702080       2016                        eng d  a1949-255300aSerum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer.0 aSerum metabolomic profiling facilitates the noninvasive identifi  c2016 Mar 15  a12904-160 v73 a<p>Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease. </p>10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aDisease Progression10aFemale10aHumans10aLung Neoplasms10aMale10ametabolomics10aMiddle Aged10aProton Magnetic Resonance Spectroscopy1 aPuchades-Carrasco, Leonor1 aJantus-Lewintre, Eloisa1 aPérez-Rambla, Clara1 aGarcia-Garcia, Francisco1 aLucas, Rut1 aCalabuig, Silvia1 aBlasco, Ana1 aDopazo, Joaquin1 aCamps, Carlos1 aPineda-Lucena, Antonio  uhttp://clinbioinfosspa.es/content/serum-metabolomic-profiling-facilitates-non-invasive-identification-metabolic-biomarkers03441nas a2200277   4500008004100000022001400041245011600055210006900171260001300240300001000253490000600263520251800269100001902787700002102806700002002827700002202847700001802869700001902887700001702906700002202923700002002945700002402965700001902989700002903008856012603037       2016                        eng d  a2212-877800aStress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.0 aStressinduced activation of brown adipose tissue prevents obesit  c2016 Jan  a19-330 v53 a<p><b>BACKGROUND: </b>Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.</p><p><b>METHODS: </b>We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.</p><p><b>RESULTS: </b>Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.</p><p><b>CONCLUSION: </b>Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.</p>1 aRazzoli, Maria1 aFrontini, Andrea1 aGurney, Allison1 aMondini, Eleonora1 aCubuk, Cankut1 aKatz, Liora, S1 aCero, Cheryl1 aBolan, Patrick, J1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aCinti, Saverio1 aBartolomucci, Alessandro  uhttp://clinbioinfosspa.es/content/stress-induced-activation-brown-adipose-tissue-prevents-obesity-conditions-low-adaptive02266nas a2200253   4500008004100000022001400041245007800055210006900133260001500202300001000217490000600227520146300233653001601696653001201712653003001724653003101754653001401785100001901799700002901818700002001847700002101867700002301888856010101911       2016                        eng d  a2045-232200aThe transcriptomics of an experimentally evolved plant-virus interaction.0 atranscriptomics of an experimentally evolved plantvirus interact  c2016 04 26  a249010 v63 a<p>Models of plant-virus interaction assume that the ability of a virus to infect a host genotype depends on the matching between virulence and resistance genes. Recently, we evolved tobacco etch potyvirus (TEV) lineages on different ecotypes of Arabidopsis thaliana, and found that some ecotypes selected for specialist viruses whereas others selected for generalists. Here we sought to evaluate the transcriptomic basis of such relationships. We have characterized the transcriptomic responses of five ecotypes infected with the ancestral and evolved viruses. Genes and functional categories differentially expressed by plants infected with local TEV isolates were identified, showing heterogeneous responses among ecotypes, although significant parallelism existed among lineages evolved in the same ecotype. Although genes involved in immune responses were altered upon infection, other functional groups were also pervasively over-represented, suggesting that plant resistance genes were not the only drivers of viral adaptation. Finally, the transcriptomic consequences of infection with the generalist and specialist lineages were compared. Whilst the generalist induced very similar perturbations in the transcriptomes of the different ecotypes, the perturbations induced by the specialist were divergent. Plant defense mechanisms were activated when the infecting virus was specialist but they were down-regulated when infecting with generalist.</p>10aArabidopsis10aEcotype10aGene Expression Profiling10aHost-Pathogen Interactions10aPotyvirus1 aHillung, Julia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aCuevas, José, M1 aElena, Santiago, F  uhttp://clinbioinfosspa.es/content/transcriptomics-experimentally-evolved-plant-virus-interaction01574nas a2200253   4500008004100000022001400041245006500055210006300120260001600183300001100199490000700210520080700217653002601024653001301050653001301063100002401076700002401100700002101124700002001145700001701165700002001182700002001202856009801222       2016                        eng d  a1367-481100aWeb-based network analysis and visualization using CellMaps.0 aWebbased network analysis and visualization using CellMaps  c2016 Oct 01  a3041-30 v323 a<p><b>UNLABELLED: </b>: CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.</p><p><b>CONTACT: </b>jdopazo@cipf.es</p><p><b>SUPPLEMENTARY INFORMATION: </b>Supplementary data are available at Bioinformatics online.</p>10aBiochemical Phenomena10aInternet10aSoftware1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aSánchez, Rubén1 aAlonso, Roberto1 aBleda, Marta1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/web-based-network-analysis-and-visualization-using-cellmaps02962nas a2200529   4500008004100000022001400041245011800055210006900173260001200242300001400254490000800268520135400276653001501630653001001645653001201655653002701667653002101694653002401715653001001739653002101749653002801770653001001798653001101808653003501819653002201854653004201876653001101918653003301929653001301962653002601975653003702001653002502038653001802063100002202081700001902103700001802122700001902140700001502159700001802174700001902192700001902211700002002230700001802250700002202268700002002290856012202310       2016                        eng d  a1432-120300aWhole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.0 aWhole exome sequencing of Rett syndromelike patients reveals the  c2016 12  a1343-13540 v1353 a<p>Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.</p>10aAdolescent10aAdult10aAnimals10aCaenorhabditis elegans10aCarrier Proteins10aCell Cycle Proteins10aChild10aChild, Preschool10aDNA Mutational Analysis10aExome10aFemale10aForkhead Transcription Factors10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aHumans10aMethyl-CpG-Binding Protein 210amutation10aNerve Tissue Proteins10aProtein Serine-Threonine Kinases10aReceptors, Nicotinic10aRett Syndrome1 aLucariello, Mario1 aVidal, Enrique1 aVidal, Silvia1 aSaez, Mauricio1 aRoa, Laura1 aHuertas, Dori1 aPineda, Mercè1 aDalfó, Esther1 aDopazo, Joaquin1 aJurado, Paola1 aArmstrong, Judith1 aEsteller, Manel  uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-rett-syndrome-patients-reveals-mutational-diversity-clinical02445nas a2200469   4500008004100000022001400041245008300055210006900138260001600207300001400223490000700237520108700244653001501331653002101346653002201367653001601389653002101405653000801426653001201434653002001446653002001466100002001486700002401506700002901530700003101559700001701590700002401607700002301631700002201654700002401676700002101700700001801721700002201739700001901761700003601780700002301816700002301839700002001862700002001882700002001902856005301922       2015                        eng d  a1362-496200aBabelomics 5.0: functional interpretation for new generations of genomic data.0 aBabelomics 50 functional interpretation for new generations of g  c2015 Apr 20  aW117-W1210 v433 aBabelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.10ababelomics10adata integration10agene set analysis10ainteractome10anetwork analysis10aNGS10aRNA-seq10aSystems biology10atranscriptomics1 aAlonso, Roberto1 aSalavert, Francisco1 aGarcia-Garcia, Francisco1 aCarbonell-Caballero, José1 aBleda, Marta1 aGarcía-Alonso, Luz1 aSanchis-Juan, Alba1 aPerez-Gil, Daniel1 aMarin-Garcia, Pablo1 aSánchez, Rubén1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aHernansaiz-Ballesteros, Rosa, D1 aAlemán, Alejandro1 aTárraga, Joaquín1 aMontaner, David1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://nar.oxfordjournals.org/content/43/W1/W11701828nas a2200253   4500008004100000022001400041245007200055210006900127260001700196300001300213490000700226520106800233653000801301653000801309653002301317100002101340700002301361700002001384700002301404700002201427700002001449700003001469856007501499       2015                        eng d  a1557-996400aConcurrent and Accurate Short Read Mapping on Multicore Processors.0 aConcurrent and Accurate Short Read Mapping on Multicore Processo  c2015 Sep-Oct  a995-10070 v123 aWe introduce a parallel aligner with a work-flow organization for fast and accurate mapping of RNA sequences on servers equipped with multicore processors. Our software, [Formula: see text] ([Formula: see text] is an open-source application. The software is available at http://www.opencb.org, exploits a suffix array to rapidly map a large fraction of the RNA fragments (reads), as well as leverages the accuracy of the Smith-Waterman algorithm to deal with conflictive reads. The aligner is enhanced with a careful strategy to detect splice junctions based on an adaptive division of RNA reads into small segments (or seeds), which are then mapped onto a number of candidate alignment locations, providing crucial information for the successful alignment of the complete reads. The experimental results on a platform with Intel multicore technology report the parallel performance of [Formula: see text], on RNA reads of 100-400 nucleotides, which excels in execution time/sensitivity to state-of-the-art aligners such as TopHat 2+Bowtie 2, MapSplice, and STAR.10aHPC10aNGS10ashort real mapping1 aMartinez, Hector1 aTárraga, Joaquín1 aMedina, Ignacio1 aBarrachina, Sergio1 aCastillo, Maribel1 aDopazo, Joaquin1 aQuintana-Orti, Enrique, S  uhttp://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=701000501072nas a2200289   4500008004100000245009100041210006900132260001600201490000600217100002300223700001900246700002600265700002500291700002700316700002000343700002000363700002600383700002600409700002300435700001700458700003600475700002000511700002500531700003400556700001900590856017300609       2015                        eng d00aExome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease0 aExome sequencing reveals a high genetic heterogeneity on familia  cJan-12-20150 v51 aLuzón-Toro, Berta1 aGui, Hongsheng1 aRuiz-Ferrer, Macarena1 aTang, Clara, Sze-Man1 aFernández, Raquel, M.1 aSham, Pak-Chung1 aTorroglosa, Ana1 aTam, Paul, Kwong-Hang1 aEspino-Paisán, Laura1 aCherny, Stacey, S.1 aBleda, Marta1 aEnguix-Riego, María, Del Valle1 aDopazo, Joaquin1 aAntiňolo, Guillermo1 aGarcia-Barceló, Maria-Mercè1 aBorrego, Salud  uhttp://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep1647302220nas a2200265   4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520128900285100002301574700002801597700002501625700002001650700002001670700001901690700002501709700002301734700002501757700002501782700002101807856012601828       2015                        eng d  a1600-072200aFamily-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.0 aFamilybased genomewide association study in Patagonia confirms t  c2015 Oct  a381-3840 v1233 a<p>The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.</p>1 aFonseca, Renata, F1 ade Carvalho, Flávia, M1 aPoletta, Fernando, A1 aMontaner, David1 aDopazo, Joaquin1 aMereb, Juan, C1 aMoreira, Miguel, A M1 aSeuanez, Hector, N1 aVieira, Alexandre, R1 aCastilla, Eduardo, E1 aOrioli, Iêda, M  uhttp://clinbioinfosspa.es/content/family-based-genome-wide-association-study-patagonia-confirms-association-dmd-locus-and02551nas a2200301   4500008004100000022001400041245008500055210006900140260001600209300000700225490000700232520160800239653001501847653001801862653001301880653004201893653001101935653002301946653002701969653001301996100002002009700002002029700002302049700002002072700002002092700002202112856011502134       2015                        eng d  a1471-210500aFast inexact mapping using advanced tree exploration on backward search methods.0 aFast inexact mapping using advanced tree exploration on backward  c2015 Jan 28  a180 v163 a<p><b>BACKGROUND: </b>Short sequence mapping methods for Next Generation Sequencing consist on a combination of seeding techniques followed by local alignment based on dynamic programming approaches. Most seeding algorithms are based on backward search alignment, using the Burrows Wheeler Transform, the Ferragina and Manzini Index or Suffix Arrays. All these backward search algorithms have excellent performance, but their computational cost highly increases when allowing errors. In this paper, we discuss an inexact mapping algorithm based on pruning strategies for search tree exploration over genomic data.</p><p><b>RESULTS: </b>The proposed algorithm achieves a 13x speed-up over similar algorithms when allowing 6 base errors, including insertions, deletions and mismatches. This algorithm can deal with 400 bps reads with up to 9 errors in a high quality Illumina dataset. In this example, the algorithm works as a preprocessor that reduces by 55% the number of reads to be aligned. Depending on the aligner the overall execution time is reduced between 20-40%.</p><p><b>CONCLUSIONS: </b>Although not intended as a complete sequence mapping tool, the proposed algorithm could be used as a preprocessing step to modern sequence mappers. This step significantly reduces the number reads to be aligned, accelerating overall alignment time. Furthermore, this algorithm could be used for accelerating the seeding step of already available sequence mappers. In addition, an out-of-core index has been implemented for working with large genomes on systems without expensive memory configurations.</p>10aAlgorithms10aGenome, Human10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Alignment10aSequence Analysis, DNA10aSoftware1 aSalavert, José1 aTomás, Andrés1 aTárraga, Joaquín1 aMedina, Ignacio1 aDopazo, Joaquin1 aBlanquer, Ignacio  uhttp://clinbioinfosspa.es/content/fast-inexact-mapping-using-advanced-tree-exploration-backward-search-methods02478nas a2200325   4500008004100000022001400041245015000055210006900205260000900274300000700283490000600290520144200296653001401738653000901752653001901761100002301780700001701803700001901820700002401839700002601863700002001889700002801909700002601937700002601963700002001989700002502009700002002034700001902054856007902073       2015                        eng d  a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.0 aIdentification of epistatic interactions through genomewide asso  c2015  a830 v83 aBACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.10aepistasis10aGWAS10aThyroid cancer1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y1 aFernández, Raquel, M1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-701498nas a2200289   4500008004100000022001400041245014900055210006900204260000800273300000700281490000600288520057300294100002300867700001700890700001900907700002400926700002600950700002000976700002800996700002701024700002701051700002001078700002501098700002001123700001901143856004601162       2015                        eng d  a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas0 aIdentification of epistatic interactions through genomewide asso  cDec  a830 v83 aThe molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y.1 aFernández, Raquel, M.1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttps://doi.org/10.1186/s12920-015-0160-701104nas a2200241   4500008004100000022001400041245015500055210006900210260000800279300000700287490000700294520032500301100001800626700002200644700002100666700002000687700002700707700002700734700001700761700002000778700001800798856004600816       2015                        eng d  a1471-216400aInvolvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation0 aInvolvement of a citrus meiotic recombination TTCrepeat motif in  cFeb  a690 v163 aTransposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored.1 aTerol, Javier1 aIbañez, Victoria1 aCarbonell, José1 aAlonso, Roberto1 aEstornell, Leandro, H.1 aLicciardello, Concetta1 aGut, Ivo, G.1 aDopazo, Joaquin1 aTalon, Manuel  uhttps://doi.org/10.1186/s12864-015-1280-302385nas a2200397   4500008004100000022001400041245007600055210006900131260001300200300001300213490000700226520116000233653001201393653001801405653002201423653002201445653002301467653002401490653002801514653003801542653001101580653002001591653002801611653001301639653002201652653001401674653003601688653003201724653002401756100002401780700002401804700001801828700002001846700001701866856010401883       2015                        eng d  a1553-735800aA Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.0 aPanCancer Catalogue of Cancer Driver Protein Interaction Interfa  c2015 Oct  ae10045180 v113 a<p>Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated. </p>10aAnimals10aBase Sequence10aBiomarkers, Tumor10aCatalogs as Topic10aChromosome Mapping10aComputer Simulation10aDNA Mutational Analysis10aGenetic Predisposition to Disease10aHumans10aModels, Genetic10aMolecular Sequence Data10amutation10aNeoplasm Proteins10aNeoplasms10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aSignal Transduction1 aPorta-Pardo, Eduard1 aGarcía-Alonso, Luz1 aHrabe, Thomas1 aDopazo, Joaquin1 aGodzik, Adam  uhttp://clinbioinfosspa.es/content/pan-cancer-catalogue-cancer-driver-protein-interaction-interfaces02086nas a2200253   4500008004100000022001400041245014200055210006900197260001600266300001400282490000700296520127300303653001601576653001101592653001401603653000801617100003101625700002001656700002201676700001801698700001801716700002001734856007801754       2015                        eng d  a1537-171900aA phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.0 aphylogenetic analysis of 34 chloroplast genomes elucidates the r  c2015 Apr 14  a2015-20350 v323 aCitrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.10achloroplast10acitrus10aPhylogeny10aWGS1 aCarbonell-Caballero, José1 aAlonso, Roberto1 aIbañez, Victoria1 aTerol, Javier1 aTalon, Manuel1 aDopazo, Joaquin  uhttp://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full02325nas a2200265   4500008004100000022001400041245012000055210006900175260001300244300001300257490000700270520140800277653002301685653001301708653003201721653004301753100001901796700001901815700001601834700002401850700002001874700002401894700001501918856012601933       2015                        eng d  a1362-496200aPTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.0 aPTMcode v2 a resource for functional associations of posttransla  c2015 Jan  aD494-5020 v433 a<p>The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300,000 experimentally verified PTMs (>1,300,000 propagated) of 69 types extracting the post-translational regulation of >100,000 proteins and >100,000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs.</p>10aDatabases, Protein10aInternet10aProtein Interaction Mapping10aProtein Processing, Post-Translational1 aMinguez, Pablo1 aLetunic, Ivica1 aParca, Luca1 aGarcía-Alonso, Luz1 aDopazo, Joaquin1 aHuerta-Cepas, Jaime1 aBork, Peer  uhttp://clinbioinfosspa.es/content/ptmcode-v2-resource-functional-associations-post-translational-modifications-within-and02531nas a2200361   4500008004100000022001400041245008000055210006900135260001300204300001300217490000800230520137100238653001801609653004901627653003401676653001701710653001101727653002801738653002301766653001301789653002501802653002701827653001001854100003301864700002301897700002801920700003301948700002201981700002002003700001902023700002502042856010202067       2015                        eng d  a1552-483300aRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.0 aReevaluation casts doubt on the pathogenicity of homozygous USH2  c2015 Jul  a1597-6000 v1673 a<p>Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.</p>10aBase Sequence10aCyclic Nucleotide Phosphodiesterases, Type 610aExtracellular Matrix Proteins10aGene Library10aHumans10aMolecular Sequence Data10aMutation, Missense10aPedigree10aRetinitis pigmentosa10aSequence Analysis, DNA10aSpain1 aDel Pozo, María, González-1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aMontero-de-Espinosa, Ignacio1 aMillán, José, M1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/re-evaluation-casts-doubt-pathogenicity-homozygous-ush2a-pc759f01866nas a2200337   4500008004100000022001400041245010900055210006900164260001600233300001000249490000600259520081400265653001501079653002601094653001501120653002101135653001801156653002001174653001101194653001901205653001401224653002001238653001301258653002401271100001901295700003001314700001901344700002401363700002001387856012101407       2015                        eng d  a2045-232200aUsing activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.0 aUsing activation status of signaling pathways as mechanismbased   c2015 Dec 18  a184940 v53 a<p>Many complex traits, as drug response, are associated with changes in biological pathways rather than being caused by single gene alterations. Here, a predictive framework is presented in which gene expression data are recoded into activity statuses of signal transduction circuits (sub-pathways within signaling pathways that connect receptor proteins to final effector proteins that trigger cell actions). Such activity values are used as features by a prediction algorithm which can efficiently predict a continuous variable such as the IC50 value. The main advantage of this prediction method is that the features selected by the predictor, the signaling circuits, are themselves rich-informative, mechanism-based biomarkers which provide insight into or drug molecular mechanisms of action (MoA). </p>10aAlgorithms10aAntineoplastic Agents10abiomarkers10aCell Line, Tumor10aCell Survival10agene expression10aHumans10aLethal Dose 5010aNeoplasms10aPhosphorylation10aProteins10aSignal Transduction1 aAmadoz, Alicia1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aSalavert, Francisco1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/using-activation-status-signaling-pathways-mechanism-based-biomarkers-predict-drug02872nas a2200373   4500008004100000022001400041245013900055210006900194260001600263300001400279490000700293520162700300100003001927700002401957700001801981700003201999700002002031700001802051700002802069700002202097700003402119700002602153700003302179700002802212700002702240700001802267700002902285700002002314700002802334700001902362700002002381700001802401856007902419       2015                        eng d  a1460-208300aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.0 aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated W  c2015 Apr 16  a4037-40480 v243 aRetinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alex1 aFernadez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W1 aCuenca, Nicolas1 aAyuso, Carmen  uhttp://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract03593nas a2200601   4500008004100000022001400041245013900055210006900194260001600263300001200279490000700291520163400298653002401932653001201956653002501968653002301993653001402016653002502030653001002055653003402065653004202099653001502141653001102156653002802167653002002195653001302215653001102228653003702239653003602276653002502312653002602337100003002363700002402393700001802417700003202435700002002467700002302487700002902510700002202539700003402561700002602595700003302621700002802654700002702682700001802709700002902727700002002756700002802776700002102804700002002825700001802845856012802863       2015                        eng d  a1460-208300aWhole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.0 aWholeexome sequencing reveals ZNF408 as a new gene associated wi  c2015 Jul 15  a4037-480 v243 a<p>Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina. </p>10aAmino Acid Sequence10aAnimals10aChlorocebus aethiops10aChromosome Mapping10aCOS Cells10aDNA-Binding Proteins10aExome10aGenome-Wide Association Study10aHigh-Throughput Nucleotide Sequencing10aHomozygote10aHumans10aMolecular Sequence Data10aMutant Proteins10aPedigree10aRetina10aRetinal Cone Photoreceptor Cells10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aTranscription Factors1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alejandro1 aFernandez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W J1 aCuenca, Nicolas1 aAyuso, Carmen  uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-reveals-znf408-new-gene-associated-autosomal-recessive-retinitis-002163nas a2200289   4500008004100000022001400041245017000055210006900225260000900294300000800303490000600311520111200317100002701429700001601456700002901472700002601501700002901527700001901556700002101575700002901596700002701625700002001652700002401672700002401696700002601720856012701746       2014                        eng d  a2234-943X00aThe Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.0 aActivation of the Sox2 RR2 Pluripotency Transcriptional Reporter  c2014  a3080 v43 a<p>The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer. </p>1 aIglesias, Juan, Manuel1 aLeis, Olatz1 aRuiz, Estíbaliz, Pérez1 aBarrie, Juan, Gumuzio1 aGarcia-Garcia, Francisco1 aAduriz, Ariane1 aBeloqui, Izaskun1 aHernandez-Garcia, Susana1 aLopez-Mato, Maria, Paz1 aDopazo, Joaquin1 aPandiella, Atanasio1 aMenendez, Javier, A1 aMartin, Angel, Garcia  uhttp://clinbioinfosspa.es/content/activation-sox2-rr2-pluripotency-transcriptional-reporter-human-breast-cancer-cell-lines02676nas a2200541   4500008004100000022001400041245013100055210006900186260000900255300000900264490000600273520115300279653001201432100002001444700002001464700001601484700001701500700002501517700001601542700002001558700001801578700002101596700001801617700002001635700002001655700002101675700001401696700001501710700001801725700001901743700002601762700002701788700002701815700001601842700001301858700002101871700002601892700001801918700001601936700001801952700001501970700001501985700001302000700001502013700001302028700001602041856007702057       2014                        eng d  a2041-172300aAssessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures.0 aAssessing technical performance in differential gene expression   c2014  a51250 v53 aThere is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard ’dashboard’ of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols.10aRNA-seq1 aMunro, Sarah, A1 aLund, Steven, P1 aPine, Scott1 aBinder, Hans1 aClevert, Djork-Arné1 aConesa, Ana1 aDopazo, Joaquin1 aFasold, Mario1 aHochreiter, Sepp1 aHong, Huixiao1 aJafari, Nadereh1 aKreil, David, P1 aLabaj, Paweł, P1 aLi, Sheng1 aLiao, Yang1 aLin, Simon, M1 aMeehan, Joseph1 aMason, Christopher, E1 aSantoyo-López, Javier1 aSetterquist, Robert, A1 aShi, Leming1 aShi, Wei1 aSmyth, Gordon, K1 aStralis-Pavese, Nancy1 aSu, Zhenqiang1 aTong, Weida1 aWang, Charles1 aWang, Jian1 aXu, Joshua1 aYe, Zhan1 aYang, Yong1 aYu, Ying1 aSalit, Marc  uhttp://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html02423nas a2200433   4500008004100000022001400041245008500055210006900140260001500209300001400224490000700238520117700245653001501422653001601437653003101453100002001484700002201504700001901526700001901545700001701564700002201581700001901603700002601622700001801648700002301666700002201689700002101711700002001732700001801752700002001770700003001790700002301820700002501843700002001868700002001888700001301908700002001921856004801941       2014                        eng d  a1538-744500aA Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition.0 aComprehensive DNA Methylation Profile of EpithelialtoMesenchymal  c2014 Aug 8  a5608–190 v743 aEpithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.10aMethyl-Seq10aMethylomics10aNext Generation Sequencing1 aCarmona, Javier1 aDavalos, Veronica1 aVidal, Enrique1 aGomez, Antonio1 aHeyn, Holger1 aHashimoto, Yutaka1 aVizoso, Miguel1 aMartinez-Cardus, Anna1 aSayols, Sergi1 aFerreira, Humberto1 aSanchez-Mut, Jose1 aMoran, Sebastian1 aMargeli, Mireia1 aCastella, Eva1 aBerdasco, Maria1 aStefansson, Olafur, Andri1 aEyfjord, Jorunn, E1 aGonzalez-Suarez, Eva1 aDopazo, Joaquin1 aOrozco, Modesto1 aGut, Ivo1 aEsteller, Manel  uhttp://www.ncbi.nlm.nih.gov/pubmed/2510642702364nas a2200265   4500008004100000022001400041245009900055210006900154260001300223300001100236490000600247520144900253100003301702700002801735700002701763700002201790700002301812700001901835700002401854700003201878700002001910700001901930700002501949856012401974       2014                        eng d  a2324-926900aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.0 aDeciphering intrafamilial phenotypic variability by exome sequen  c2014 Mar  a124-330 v23 a<p>Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability. </p>1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/deciphering-intrafamilial-phenotypic-variability-exome-sequencing-bardet-biedl-family02775nas a2200445   4500008004100000022001400041245012000055210006900175260000900244300001200253490000600265520144600271653001501717653001001732653002401742653001801766653001001784653002701794653002801821653001001849653001101859653001101870653001101881653002501892653000901917653001601926653002801942653001301970653001301983653002401996653001402020100003302034700002802067700002302095700002202118700002002140700001902160700002502179856012502204       2014                        eng d  a1932-620300aExome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.0 aExome sequencing reveals novel and recurrent mutations with clin  c2014  ae1161760 v93 a<p>This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program. </p>10aAdolescent10aAdult10aAmino Acid Sequence10aBase Sequence10aChild10aChromosome Segregation10aDNA Mutational Analysis10aExome10aFamily10aFemale10aHumans10aInheritance Patterns10aMale10aMiddle Aged10aMolecular Sequence Data10amutation10aPedigree10aRetinal Dystrophies10aRhodopsin1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/exome-sequencing-reveals-novel-and-recurrent-mutations-clinical-significance-inherited01427nas a2200229   4500008004100000022001400041245005200055210005100107260001600158300001100174490000700185520080300192653002000995653001901015653002301034653001701057653001301074653002101087653002101108100002001129856004801149       2014                        eng d  a1878-583200aGenomics and transcriptomics in drug discovery.0 aGenomics and transcriptomics in drug discovery  c2013 Jun 14  a126-320 v193 aThe popularization of genomic high-throughput technologies is causing a revolution in biomedical research and, particularly, is transforming the field of drug discovery. Systems biology offers a framework to understand the extensive human genetic heterogeneity revealed by genomic sequencing in the context of the network of functional, regulatory and physical protein-drug interactions. Thus, approaches to find biomarkers and therapeutic targets will have to take into account the complex system nature of the relationships of the proteins with the disease. Pharmaceutical companies will have to reorient their drug discovery strategies considering the human genetic heterogeneity. Consequently, modeling and computational data analysis will have an increasingly important role in drug discovery.10aadverse effects10aDrug discovery10adrug repositioning10ametagenomics10amodeling10anetwork analysis10apathway analysis1 aDopazo, Joaquin  uhttp://www.ncbi.nlm.nih.gov/pubmed/2377386001909nas a2200265   4500008004100000022001400041245007900055210006900134260001600203300001100219490000700230520106400237653001001301653001801311653004201329653001101371653002701382653001301409100003301422700002301455700001901478700002001497700002701517856009901544       2014                        eng d  a1367-481100angsCAT: a tool to assess the efficiency of targeted enrichment sequencing.0 angsCAT a tool to assess the efficiency of targeted enrichment se  c2014 Jun 15  a1767-80 v303 a<p><b>MOTIVATION: </b>Targeted enrichment sequencing by next-generation sequencing is a common approach to interrogate specific loci or the whole exome in the human genome. The efficiency and the lack of bias in the enrichment process need to be assessed as a quality control step before performing downstream analysis of the sequence data. Tools that can report on the sensitivity, specificity, uniformity and other enrichment-specific features are needed.</p><p><b>RESULTS: </b>We have implemented the next-generation sequencing data Capture Assessment Tool (ngsCAT), a tool that takes the information of the mapped reads and the coordinates of the targeted regions as input files, and generates a report with metrics and figures that allows the evaluation of the efficiency of the enrichment process. The tool can also take as input the information of two samples allowing the comparison of two different experiments.</p><p><b>AVAILABILITY AND IMPLEMENTATION: </b>Documentation and downloads for ngsCAT can be found at http://www.bioinfomgp.org/ngscat.</p>10aExome10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Analysis, DNA10aSoftware1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aRueda, Antonio1 aDopazo, Joaquin1 aSantoyo-López, Javier  uhttp://clinbioinfosspa.es/content/ngscat-tool-assess-efficiency-targeted-enrichment-sequencing03760nas a2200397   4500008004100000022001400041245013500055210006900190260001600259300000800275490000700283520244800290653002602738653001802764653002502782653002802807653001702835653002102852653003202873653001102905653002702916653003602943653002302979653001303002653001403015653001103029653002503040100002803065700002303093700003303116700002203149700002003171700001903191700002503210856012703235       2014                        eng d  a1471-215600aNovel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.0 aNovel RP1 mutations and a recurrent BBS1 variant explain the coe  c2014 Dec 14  a1430 v153 a<p><b>BACKGROUND: </b>Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).</p><p><b>RESULTS: </b>Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.</p><p><b>CONCLUSIONS: </b>The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.</p>10aBardet-Biedl Syndrome10aBase Sequence10aCase-Control Studies10aDNA Mutational Analysis10aEye Proteins10aGenes, Recessive10aGenetic Association Studies10aHumans10aMicrosatellite Repeats10aMicrotubule-Associated Proteins10aMutation, Missense10aPedigree10aPhenotype10aRetina10aRetinitis pigmentosa1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/novel-rp1-mutations-and-recurrent-bbs1-variant-explain-co-existence-two-distinct-retinal03070nas a2200385   4500008004100000022001400041245005700055210005600112260000900168300000700177490001400184520197500198653002202173653001502195653002002210653003002230653002902260653002002289653001502309653003002324653001602354653001202370653002902382653002002411653001402431100002102445700001802466700002002484700001802504700002002522700002102542700002002563700001602583856008502599       2014                        eng d  a1752-050900aPathway network inference from gene expression data.0 aPathway network inference from gene expression data  c2014  aS70 v8 Suppl 23 a<p><b>BACKGROUND: </b>The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules.</p><p><b>RESULTS: </b>We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example.</p><p><b>CONCLUSIONS: </b>PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data.</p>10aAlzheimer Disease10aCell Cycle10aDNA Replication10aGene Expression Profiling10aGene Regulatory Networks10aGluconeogenesis10aGlycolysis10aOxidative Phosphorylation10aProteolysis10aPurines10aSaccharomyces cerevisiae10aSystems biology10aUbiquitin1 aPonzoni, Ignacio1 aNueda, María1 aTarazona, Sonia1 aGötz, Stefan1 aMontaner, David1 aDussaut, Julieta1 aDopazo, Joaquin1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/pathway-network-inference-gene-expression-data02515nas a2200445   4500008004100000022001400041245009400055210006900149260000900218300001200227490000600239520119500245653001201440653001501452653001901467653001601486653002701502653002101529653001101550653002901561653001601590653001001606653003001616653001501646653001301661653001401674653001201688653001501700100001801715700002801733700003301761700002001794700002901814700001801843700002401861700002001885700002301905700002201928856011901950       2014                        eng d  a1932-620300aPermanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.0 aPermanent cardiac sarcomere changes in a rabbit model of intraut  c2014  ae1130670 v93 a<p><b>BACKGROUND: </b>Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.</p><p><b>METHODS AND RESULTS: </b>IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.</p><p><b>CONCLUSION: </b>The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.</p>10aAnimals10abiomarkers10aBlood Pressure10aBody Weight10aDisease Models, Animal10aEchocardiography10aFemale10aFetal Growth Retardation10aFetal Heart10aFetus10aGene Expression Profiling10aOrgan Size10aPlacenta10aPregnancy10aRabbits10aSarcomeres1 aTorre, Iratxe1 aGonzález-Tendero, Anna1 aGarcía-Cañadilla, Patricia1 aCrispi, Fátima1 aGarcia-Garcia, Francisco1 aBijnens, Bart1 aIruretagoyena, Igor1 aDopazo, Joaquin1 aAmat-Roldán, Ivan1 aGratacós, Eduard  uhttp://clinbioinfosspa.es/content/permanent-cardiac-sarcomere-changes-rabbit-model-intrauterine-growth-restriction02932nas a2200397   4500008004100000022001400041245010000055210006900155260001600224300000800240490000700248520172500255653001201980653001001992653001702002653002202019653002502041653001802066653001302084653001102097653002002108653001302128653001402141653002502155653002902180653002702209653001102236100002402247700002902271700003102300700002202331700002702353700002502380700002002405856010902425       2014                        eng d  a1744-429200aThe role of the interactome in the maintenance of deleterious variability in human populations.0 arole of the interactome in the maintenance of deleterious variab  c2014 Sep 26  a7520 v103 a<p>Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins. </p>10aAlleles10aExome10aGene Library10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aModels, Genetic10amutation10aPhenotype10aProtein Conformation10aProtein Interaction Maps10aSequence Analysis, DNA10aWhites1 aGarcía-Alonso, Luz1 aJiménez-Almazán, Jorge1 aCarbonell-Caballero, José1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aAntiňolo, Guillermo1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/role-interactome-maintenance-deleterious-variability-human-populations02920nas a2200409   4500008004100000022001400041245011400055210006900169260001300238300001000251490000700261520165700268653001201925653001501937653001101952653003901963653001802002653001902020653001202039653003102051653001302082653000902095653001402104653001602118653002702134653002402161653001802185100002102203700002502224700003102249700001602280700002002296700001802316700002502334700003202359856011902391       2014                        eng d  a1096-093700aSequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia.0 aSequencing and functional analysis of the genome of a nematode e  c2014 Apr  a69-800 v653 a<p>Pochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled ∼41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65%) were functionally annotated according to Gene Ontology, and 16% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.</p>10aAnimals10aAscomycota10aFemale10aGene Expression Regulation, Fungal10aGene ontology10aGenome, Fungal10aHordeum10aHost-Pathogen Interactions10aNematoda10aOvum10aPhylogeny10aPlant Roots10aSequence Analysis, DNA10aSignal Transduction10aTranscriptome1 aLarriba, Eduardo1 aJaime, María, D L A1 aCarbonell-Caballero, José1 aConesa, Ana1 aDopazo, Joaquin1 aNislow, Corey1 aMartín-Nieto, José1 aLopez-Llorca, Luis, Vicente  uhttp://clinbioinfosspa.es/content/sequencing-and-functional-analysis-genome-nematode-egg-parasitic-fungus-pochonia03195nas a2200517   4500008004100000022001400041245017300055210006900228260001300297300001000310490000700320520152000327653003201847653003101879653001601910653001101926653000901937653002301946653002801969653001501997653002002012100002802032700002302060700001602083700002402099700002502123700002102148700001902169700002202188700002102210700002002231700002002251700002202271700001902293700002102312700002802333700002202361700002002383700001702403700002702420700002602447700002102473700002402494700002802518856013102546       2014                        eng d  a1098-100400aTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.0 aTwo novel mutations in the BCKDK branchedchain ketoacid dehydrog  c2014 Apr  a470-70 v353 a<p>Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. </p>10aAmino Acids, Branched-Chain10aDevelopmental Disabilities10aFibroblasts10aHumans10aMale10aMutation, Missense10aNervous System Diseases10aPediatrics10aProtein Kinases1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquin1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar1 aAlcaide, Patricia1 aNavarrete, Rosa1 aSanz, Paloma1 aFont-Llitjós, Mariona1 aVilaseca, Ma, Antonia1 aOrmaizabal, Aida1 aPristoupilova, Anna1 aAgulló, Sergi, Beltran  uhttp://clinbioinfosspa.es/content/two-novel-mutations-bckdk-branched-chain-keto-acid-dehydrogenase-kinase-gene-are-responsible00801nas a2200241   4500008004100000245008100041210006900122260000700191300000800198490000600206100003000212700001900242700001900261700001600280700002000296700001900316700001900335700003200354700002400386700002000410700002000430856010900450       2014                        eng d00aUnderstanding disease mechanisms with models of signaling pathway activities0 aUnderstanding disease mechanisms with models of signaling pathwa  c10  a1210 v81 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aTorres, Francisco, Salavert1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/understanding-disease-mechanisms-models-signaling-pathway-activities-102637nas a2200397   4500008004100000022001400041245009900055210006900154260000900223300001100232490000600243520136900249653003101618653001601649653002501665653002601690653002501716653003001741653002901771653001801800653001101818653003401829653002701863653002601890100001801916700002601934700002401960700002001984700001702004700001902021700002002040700002002060700001602080700001802096856012502114       2013                        eng d  a1932-620300aDefining the genomic signature of totipotency and pluripotency during early human development.0 aDefining the genomic signature of totipotency and pluripotency d  c2013  ae621350 v83 a<p>The genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions.</p>10aBlastocyst Inner Cell Mass10aBlastomeres10aCell Differentiation10aEmbryonic Development10aEmbryonic Stem Cells10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aHumans10aMolecular Sequence Annotation10aPluripotent Stem Cells10aTotipotent Stem Cells1 aGalan, Amparo1 aDiaz-Gimeno, Patricia1 aPoo, Maria, Eugenia1 aValbuena, Diana1 aSanchez, Eva1 aRuiz, Veronica1 aDopazo, Joaquin1 aMontaner, David1 aConesa, Ana1 aSimon, Carlos  uhttp://clinbioinfosspa.es/content/defining-genomic-signature-totipotency-and-pluripotency-during-early-human-development02655nas a2200421   4500008004100000022001400041245010400055210006900159260001700228300000900245490000800254520136600262653001501628653001001643653003201653653001001685653001001695653001101705653004201716653001101758653001101769653000901780653003001789653001301819100001901832700003401851700002701885700002601912700002801938700002301966700001901989700002902008700002002037700001702057700001802074700001902092856012202111       2013                        eng d  a1096-720600aExome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.0 aExome sequencing identifies a new mutation in SERAC1 in a patien  c2013 Sep-Oct  a73-70 v1103 a<p>3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available. </p>10aAdolescent10aAdult10aCarboxylic Ester Hydrolases10aChild10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aMale10aMetabolism, Inborn Errors10amutation1 aTort, Frederic1 aGarcía-Silva, María, Teresa1 aFerrer-Cortès, Xènia1 aNavarro-Sastre, Aleix1 aGarcia-Villoria, Judith1 aColl, Maria, Josep1 aVidal, Enrique1 aJiménez-Almazán, Jorge1 aDopazo, Joaquin1 aBriones, Paz1 aElpeleg, Orly1 aRibes, Antonia  uhttp://clinbioinfosspa.es/content/exome-sequencing-identifies-new-mutation-serac1-patient-3-methylglutaconic-aciduria03042nas a2200481   4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520158000283653001201863653001701875653001601892653001901908653001501927653002701942653002501969653001801994653002402012653002002036653001302056653001702069653002502086653002202111653002102133653000902154653000902163653001802172653001002190100002602200700002302226700002002249700002402269700002902293700002002322700002102342700002902363700002202392700002002414856012602434       2013                        eng d  a1460-218000aGrape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber inhibits intestinal polyposis in  c2013 Aug  a1881-80 v343 a<p>Epidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65%), 1-2mm (67%) and >2mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer. </p>10aAnimals10aAntioxidants10aBody Weight10aCarcinogenesis10aCell Cycle10aCell Cycle Checkpoints10aColorectal Neoplasms10aDietary Fiber10aDietary Supplements10aDown-Regulation10aG1 Phase10aInflammation10aIntestinal Polyposis10aIntestinal Polyps10aIntestine, Small10aMale10aMice10aTranscriptome10aVitis1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, P1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aTorres, Josep, L1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta  uhttp://clinbioinfosspa.es/content/grape-antioxidant-dietary-fiber-inhibits-intestinal-polyposis-apcmin-mice-relation-cell02226nas a2200313   4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520127400241653001201515653001101527653001301538653000901551653002401560653002801584653002401612653001301636653001801649100003001667700002101697700002401718700002101742700002001763700002001783856010901803       2013                        eng d  a1362-496200aInferring the functional effect of gene expression changes in signaling pathways.0 aInferring the functional effect of gene expression changes in si  c2013 Jul  aW213-70 v413 a<p>Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/. </p>10aAnimals10aHumans10aInternet10aMice10aModels, Statistical10aReceptors, Cell Surface10aSignal Transduction10aSoftware10aTranscriptome1 aSebastián-Leon, Patricia1 aCarbonell, José1 aSalavert, Francisco1 aSánchez, Rubén1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/inferring-functional-effect-gene-expression-changes-signaling-pathways02909nas a2200373   4500008004100000022001400041245016200055210006900217260001300286300001300299490000800312520168000320653001202000653002702012653002202039653001102061653002902072653002002101653001702121653001502138653003002153653001302183653001402196653001202210100002802222700001802250700003302268700002002301700002902321700002002350700001802370700002202388856012502410       2013                        eng d  a1522-153900aIntrauterine growth restriction is associated with cardiac ultrastructural and gene expression changes related to the energetic metabolism in a rabbit model.0 aIntrauterine growth restriction is associated with cardiac ultra  c2013 Dec  aH1752-600 v3053 a<p>Intrauterine growth restriction (IUGR) affects 7-10% of pregnancies and is associated with cardiovascular remodeling and dysfunction, which persists into adulthood. The underlying subcellular remodeling and cardiovascular programming events are still poorly documented. Cardiac muscle is central in the fetal adaptive mechanism to IUGR given its high energetic demands. The energetic homeostasis depends on the correct interaction of several molecular pathways and the adequate arrangement of intracellular energetic units (ICEUs), where mitochondria interact with the contractile machinery and the main cardiac ATPases to enable a quick and efficient energy transfer. We studied subcellular cardiac adaptations to IUGR in an experimental rabbit model. We evaluated the ultrastructure of ICEUs with transmission electron microscopy and observed an altered spatial arrangement in IUGR, with significant increases in cytosolic space between mitochondria and myofilaments. A global decrease of mitochondrial density was also observed. In addition, we conducted a global gene expression profile by advanced bioinformatics tools to assess the expression of genes involved in the cardiomyocyte energetic metabolism and identified four gene modules with a coordinated over-representation in IUGR: oxygen homeostasis (GO: 0032364), mitochondrial respiratory chain complex I (GO:0005747), oxidative phosphorylation (GO: 0006119), and NADH dehydrogenase activity (GO:0003954). These findings might contribute to changes in energetic homeostasis in IUGR. The potential persistence and role of these changes in long-term cardiovascular programming deserves further investigation. </p>10aAnimals10aDisease Models, Animal10aEnergy Metabolism10aFemale10aFetal Growth Retardation10agene expression10aMitochondria10aMyocardium10aOxidative Phosphorylation10aPlacenta10aPregnancy10aRabbits1 aGonzález-Tendero, Anna1 aTorre, Iratxe1 aGarcía-Cañadilla, Patricia1 aCrispi, Fátima1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aBijnens, Bart1 aGratacós, Eduard  uhttp://clinbioinfosspa.es/content/intrauterine-growth-restriction-associated-cardiac-ultrastructural-and-gene-expression02926nas a2200445   4500008004100000022001400041245009600055210006900151260000900220300001100229490000600240520152900246653002101775653001401796653002101810653002301831653002101854653001101875653002001886653003001906653004301936653003001979653001102009653001602020653002602036653002402062653002602086100002702112700002102139700002902160700001602189700003002205700002002235700001702255700001802272700002402290700002002314700002102334856012502355       2013                        eng d  a1932-620300aMammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.0 aMammosphere formation in breast carcinoma cell lines depends upo  c2013  ae772810 v83 a<p>Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.</p>10aBreast Neoplasms10aCadherins10aCell Line, Tumor10aCell Proliferation10aCluster Analysis10aFemale10agene expression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Knockdown Techniques10aHumans10aMCF-7 Cells10aNeoplastic Stem Cells10aSpheroids, Cellular10aTumor Cells, Cultured1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A1 aDopazo, Joaquin1 aMartin, Angel, G  uhttp://clinbioinfosspa.es/content/mammosphere-formation-breast-carcinoma-cell-lines-depends-upon-expression-e-cadherin-002347nas a2200253   4500008004100000245009500041210006900136260004200205300001300247490000600260520152900266100002701795700002101822700002901843700001601872700003001888700002001918700001701938700001801955700002501973700002001998700002202018856005302040       2013                        eng d00aMammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin0 aMammosphere Formation in Breast Carcinoma Cell Lines Depends upo  bPublic Library of Sciencec2013/10/04  ae77281 -0 v83 a<p>Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.</p>1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A.1 aDopazo, Joaquin1 aMartin, Angel, G.  uhttp://dx.doi.org/10.1371%2Fjournal.pone.007728102952nas a2200481   4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520141700293653002801710653002501738653001001763653001501773653001601788653002001804653002001824653003001844653001101874653000901885653001601894653004401910653001901954653001801973100002401991700002402015700002602039700002502065700002402090700002202114700001802136700002002154700002902174700002902203700001802232700002402250700002402274700002502298700002102323856012602344       2013                        eng d  a1873-349200aNovel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.0 aNovel genes detected by transcriptional profiling from wholebloo  c2013 Jun 05  a184-900 v4213 a<p><b>BACKGROUND: </b>Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.</p><p><b>METHODS AND RESULTS: </b>This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.</p><p><b>CONCLUSIONS: </b>Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.</p>10aAcute Coronary Syndrome10aAcute-Phase Proteins10aAdult10abiomarkers10aBlood Cells10aEarly Diagnosis10agene expression10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aTranscriptome1 aSilbiger, Vivian, N1 aLuchessi, André, D1 aHirata, Rosário, D C1 aLima-Neto, Lídio, G1 aCavichioli, Débora1 aCarracedo, Ángel1 aBrión, Maria1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aSantos, Elizabete, S Dos1 aRamos, Rui, F1 aSampaio, Marcelo, F1 aArmaganijan, Dikran1 aSousa, Amanda, G M R1 aHirata, Mario, H  uhttp://clinbioinfosspa.es/content/novel-genes-detected-transcriptional-profiling-whole-blood-cells-patients-early-onset-002672nas a2200409   4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856009502167       2013                        eng d  a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease  c2013 Dec 02  a1870 v83 a<p>Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations. </p>10aFemale10aGenetic Predisposition to Disease10aGenotype10aHirschsprung Disease10aHumans10aMale10aPolymorphism, Single Nucleotide1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02722nas a2200505   4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012402092       2013                        eng d  a1600-062500aRole of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.0 aRole of CPI17 in restoring skin homoeostasis in cutaneous field   c2013 Jul  a494-60 v223 a<p>Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions. </p>10aAdministration, Topical10aAdult10aAged10aAged, 80 and over10aBiopsy10aDeoxyribodipyrimidine Photo-Lyase10aFemale10aGene Expression Profiling10aGene Expression Regulation, Enzymologic10aGene Expression Regulation, Neoplastic10aHomeostasis10aHumans10aInflammation10aIntracellular Signaling Peptides and Proteins10aLiposomes10aMale10aMiddle Aged10aMuscle Proteins10aPhenotype10aPhosphoprotein Phosphatases10aReactive Oxygen Species10aSkin10aSkin Neoplasms10aUltraviolet Rays1 aPuig-Butille, Joan, Anton1 aMalvehy, Josep1 aPotrony, Miriam1 aTrullas, Carles1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aPuig, Susana  uhttp://clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical03066nas a2200241   4500008004100000022001400041245015200055210006900207260000900276300001200285490000700297520223800304100002802542700003302570700002202603700002702625700003302652700003202685700002002717700001902737700002502756856004302781       2013                        eng d  a1090-053500aWhole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.0 aWholeexome sequencing identifies novel compound heterozygous mut  c2013  a2187-950 v193 aPURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aLópez-Domingo, Francisco, J1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttp://www.molvis.org/molvis/v19/2187/02076nas a2200241   4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520129000296100001701586700002301603700002401626700002401650700002401674700001901698700001901717700002001736700002001756856005801776       2012                        eng d  a1362-496200aCellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.0 aCellBase a comprehensive collection of RESTful web services for   c2012 Jul  aW609-140 v403 aDuring the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.1 aBleda, Marta1 aTárraga, Joaquín1 aDe Maria, Alejandro1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aCelma, Matilde1 aMartin, Ainoha1 aDopazo, Joaquin1 aMedina, Ignacio  uhttp://nar.oxfordjournals.org/content/40/W1/W609.long02616nas a2200325   4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520154400277653002101821653001901842653002901861653002001890653003401910653001301944653001101957653003201968100002402000700002002024700001902044700001902063700002402082700001902106700002002125700002002145856012502165       2012                        eng d  a1362-496200aDiscovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.0 aDiscovering the hidden subnetwork component in a ranked list of   c2012 Nov 01  ae1580 v403 a<p>Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.</p>10aBipolar Disorder10aFanconi Anemia10aGene Regulatory Networks10aGenes, Neoplasm10aGenome-Wide Association Study10aGenomics10aHumans10aProtein Interaction Mapping1 aGarcía-Alonso, Luz1 aAlonso, Roberto1 aVidal, Enrique1 aAmadoz, Alicia1 aDe Maria, Alejandro1 aMinguez, Pablo1 aMedina, Ignacio1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/discovering-hidden-sub-network-component-ranked-list-genes-or-proteins-derived-genomic03458nas a2200469   4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520195800265653002402223653001202247653001802259653002502277653001802302653001802320653001702338653003002355653002202385653001002407653001602417653003102433653002202464653002802486653002102514653001402535653003202549653005202581653002302633653002702656653003402683653001602717653002402733653001102757100002602768700002102794700002002815700002602835856012702861       2012                        eng d  a1471-214800aDiversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua.0 aDiversification of the expanded teleostspecific tolllike recepto  c2012 Dec 29  a2560 v123 a<p><b>BACKGROUND: </b>Toll-like receptors (Tlrs) are major molecular pattern recognition receptors of the innate immune system. Atlantic cod (Gadus morhua) is the first vertebrate known to have lost most of the mammalian Tlr orthologues, particularly all bacterial recognising and other cell surface Tlrs. On the other hand, its genome encodes a unique repertoire of teleost-specific Tlrs. The aim of this study was to investigate if these duplicate Tlrs have been retained through adaptive evolution to compensate for the lack of other cell surface Tlrs in the cod genome.</p><p><b>RESULTS: </b>In this study, one tlr21, 12 tlr22 and two tlr23 genes representing the teleost-specific Tlr family have been cloned and characterised in cod. Phylogenetic analysis grouped all tlr22 genes under a single clade, indicating that the multiple cod paralogues have arisen through lineage-specific duplications. All tlrs examined were transcribed in immune-related tissues as well as in stomach, gut and gonads of adult cod and were differentially expressed during early development. These tlrs were also differentially regulated following immune challenge by immersion with Vibrio anguillarum, indicating their role in the immune response. An increase in water temperature from 4 to 12°C was associated with a 5.5-fold down-regulation of tlr22d transcript levels in spleen. Maximum likelihood analysis with different evolution models revealed that tlr22 genes are under positive selection. A total of 24 codons were found to be positively selected, of which 19 are in the ligand binding region of ectodomain.</p><p><b>CONCLUSION: </b>Positive selection pressure coupled with experimental evidence of differential expression strongly support the hypothesis that teleost-specific tlr paralogues in cod are undergoing neofunctionalisation and can recognise bacterial pathogen-associated molecular patterns to compensate for the lack of other cell surface Tlrs.</p>10aAmino Acid Sequence10aAnimals10aBinding Sites10aEvolution, Molecular10aFish Diseases10aFish Proteins10aGadus morhua10aGene Expression Profiling10aGenetic Variation10aGills10aHead Kidney10aHost-Pathogen Interactions10aModels, Molecular10aMolecular Sequence Data10aMultigene Family10aPhylogeny10aProtein Structure, Tertiary10aReverse Transcriptase Polymerase Chain Reaction10aSelection, Genetic10aSequence Analysis, DNA10aSequence Homology, Amino Acid10aTemperature10aToll-Like Receptors10aVibrio1 aSundaram, Arvind, Y M1 aKiron, Viswanath1 aDopazo, Joaquin1 aFernandes, Jorge, M O  uhttp://clinbioinfosspa.es/content/diversification-expanded-teleost-specific-toll-receptor-family-atlantic-cod-gadus-morhua02970nas a2200313   4500008004100000022001400041245008300055210006900138260000900207300001100216490000600227520199700233653001202230653003302242653001102275653001702286653000902303653001802312653004402330653002502374653001902399653002702418100001902445700001902464700002002483700002002503700002002523856011302543       2012                        eng d  a1932-620300aExtensive translatome remodeling during ER stress response in mammalian cells.0 aExtensive translatome remodeling during ER stress response in ma  c2012  ae359150 v73 a<p>In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ∼10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ∼800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ∼50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5'UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5'UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed.</p>10aAnimals10aEndoplasmic Reticulum Stress10aHumans10aJurkat Cells10aMice10aNIH 3T3 Cells10aOligonucleotide Array Sequence Analysis10aProtein Biosynthesis10aRNA, Messenger10aTranscription, Genetic1 aVentoso, Iván1 aKochetov, Alex1 aMontaner, David1 aDopazo, Joaquin1 aSantoyo, Javier  uhttp://clinbioinfosspa.es/content/extensive-translatome-remodeling-during-er-stress-response-mammalian-cells02486nas a2200373   4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856012501987       2012                        eng d  a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.0 aFour new loci associations discovered by pathwaybased and networ  c2012 Dec 28  a1030 v73 a<p>Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.</p>10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHirschsprung Disease10aHumans10aMale1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud  uhttp://clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-003355nas a2200529   4500008004100000022001400041245009200055210007000147260001300217300001100230490000600241520169800247653001801945653001801963653002301981653001502004653002602019653001302045653001702058653003002075653003002105653001702135653001102152653002102163653002702184653005002211653002202261653001202283653001502295653002702310653001502337653004402352653002102396653002402417100002002441700002402461700001802485700002002503700002902523700002002552700002202572700002302594700002302617700003002640700002202670856013302692       2012                        eng d  a2629-327700aIL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.0 aIL1β induces mesenchymal stem cells migration and leucocyte chem  c2012 Sep  a905-160 v83 a<p>Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.</p>10aCell Adhesion10aCell Movement10aCell Proliferation10aChemokines10aChemotaxis, Leukocyte10aCollagen10aFibronectins10aGene Expression Profiling10aGene Knockdown Techniques10aHEK293 Cells10aHumans10aI-kappa B Kinase10aInflammation Mediators10aIntercellular Signaling Peptides and Proteins10aInterleukin-1beta10aLaminin10aLeukocytes10aMesenchymal Stem Cells10aNF-kappa B10aOligonucleotide Array Sequence Analysis10aRNA Interference10aSignal Transduction1 aCarrero, Rubén1 aCerrada, Inmaculada1 aLledó, Elisa1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aRubio, Mari-Paz1 aTrigueros, César1 aDorronsoro, Akaitz1 aRuiz-Sauri, Amparo1 aMontero, José, Anastasio1 aSepúlveda, Pilar  uhttp://clinbioinfosspa.es/content/il1%CE%B2-induces-mesenchymal-stem-cells-migration-and-leucocyte-chemotaxis-through-nf-%CE%BAb01996nas a2200313   4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520105300230653001801283653002301301653001901324653002901343653001301372653001401385653001301399653002601412653001801438100001701456700002001473700002001493700002401513700002401537700002001561856010101581       2012                        eng d  a1362-496200aInferring the regulatory network behind a gene expression experiment.0 aInferring the regulatory network behind a gene expression experi  c2012 Jul  aW168-720 v403 a<p>Transcription factors (TFs) and miRNAs are the most important dynamic regulators in the control of gene expression in multicellular organisms. These regulatory elements play crucial roles in development, cell cycling and cell signaling, and they have also been associated with many diseases. The Regulatory Network Analysis Tool (RENATO) web server makes the exploration of regulatory networks easy, enabling a better understanding of functional modularity and network integrity under specific perturbations. RENATO is suitable for the analysis of the result of expression profiling experiments. The program analyses lists of genes and search for the regulators compatible with its activation or deactivation. Tests of single enrichment or gene set enrichment allow the selection of the subset of TFs or miRNAs significantly involved in the regulation of the query genes. RENATO also offers an interactive advanced graphical interface that allows exploring the regulatory network found.RENATO is available at: http://renato.bioinfo.cipf.es/.</p>10aBinding Sites10aDatabases, Genetic10aFanconi Anemia10aGene Regulatory Networks10aInternet10aMicroRNAs10aSoftware10aTranscription Factors10aTranscriptome1 aBleda, Marta1 aMedina, Ignacio1 aAlonso, Roberto1 aDe Maria, Alejandro1 aSalavert, Francisco1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/inferring-regulatory-network-behind-gene-expression-experiment02674nas a2200313   4500008004100000022001400041245008800055210006900143260001600212300000700228490000600235520174000241653000801981100002101989700001602010700001602026700001902042700002002061700002602081700002002107700002902127700002802156700003302184700001702217700002702234700002502261700002002286856005402306       2012                        eng d  a1756-994X00aA map of human microRNA variation uncovers unexpectedly high levels of variability.0 amap of human microRNA variation uncovers unexpectedly high level  c2012 Aug 20  a620 v43 aABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.10aNGS1 aCarbonell, José1 aAlloza, Eva1 aArce, Pablo1 aBorrego, Salud1 aSantoyo, Javier1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aJiménez-Almazán, Jorge1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela, Alicia1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo1 aDopazo, Joaquin  uhttp://genomemedicine.com/content/4/8/62/abstract02563nas a2200445   4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520111500256653001201371653002201383653003901405653002601444653002201470653004401492653001701536653003201553653000901585653002701594653005201621653002101673653002701694653001801721653003201739100002201771700001901793700001501812700002001827700002201847700001901869700002001888700002001908700002201928700002101950700002201971856012401993       2012                        eng d  a1530-686000aThe protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.0 aprotease MT1MMP drives a combinatorial proteolytic program in ac  c2012 Nov  a4481-940 v263 a<p>The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.</p>10aAnimals10aBlotting, Western10aCombinatorial Chemistry Techniques10aComputational Biology10aEndothelial Cells10aGene Expression Regulation, Enzymologic10aInflammation10aMatrix Metalloproteinase 1410aMice10aProtein Array Analysis10aReverse Transcriptase Polymerase Chain Reaction10aRNA Interference10aRNA, Small Interfering10aTranscriptome10aTumor Necrosis Factor-alpha1 aKoziol, Agnieszka1 aGonzalo, Pilar1 aMota, Alba1 aPollán, Angela1 aLorenzo, Cristina1 aColomé, Nuria1 aMontaner, David1 aDopazo, Joaquin1 aArribas, Joaquín1 aCanals, Francesc1 aArroyo, Alicia, G  uhttp://clinbioinfosspa.es/content/protease-mt1-mmp-drives-combinatorial-proteolytic-program-activated-endothelial-cells02231nas a2200325   4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520119100257653002301448653001101471653001301482653002701495653001401522653003601536653002501572653001301597100002001610700002101630700001801651700002801669700001801697700002001715700002301735700002301758856012401781       2012                        eng d  a1362-496200aSNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.0 aSNPeffect 40 online prediction of molecular and structural effec  c2012 Jan  aD935-90 v403 a<p>Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.</p>10aDatabases, Protein10aHumans10aInternet10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Conformation10aProteins1 aDe Baets, Greet1 aVan Durme, Joost1 aReumers, Joke1 aMaurer-Stroh, Sebastian1 aVanhee, Peter1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic  uhttp://clinbioinfosspa.es/content/snpeffect-40-line-prediction-molecular-and-structural-effects-protein-coding-variants02754nas a2200217   4500008004100000022001400041245012800055210006900183260000900252300000700261490000600268520203200274100002702306700003302333700003002366700002902396700002002425700001602445700001802461856005702479       2012                        eng d  a2193-180100aTransdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.0 aTransdifferentiation of MALME3M and MCF7 Cells toward Adipocytel  c2012  a440 v13 aABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".1 aCarcel-Trullols, Jaime1 aAguilar-Gallardo, Cristóbal1 aGarcía-Alcalde, Fernando1 aPardo-Cea, Miguel, Angel1 aDopazo, Joaquin1 aConesa, Ana1 aSimon, Carlos  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/01857nas a2200265   4500008004100000022001400041245011600055210006900171260001600240300001400256490000600270520098400276653003001260653001801290653001001308653000801318100002701326700003001353700002901383700002301412700002001435700002101455700002001476856009501496       2012                        eng d  a1557-996400aUsing GPUs for the Exact Alignment of Short-read Genetic Sequences by Means of the Burrows–Wheeler Transform.0 aUsing GPUs for the Exact Alignment of Shortread Genetic Sequence  c2012 Mar 20  a1245-12560 v93 aGeneral Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows-Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12x, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximising memory locality and ensuring a symmetric access to the data. The article describes the behaviour of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.10aBurrows-Wheeler transform10aCPU execution10aGPGPU10aNGS1 aTorres, Jose, Salavert1 aEspert, Ignacio, Blanquer1 aDominguez, Andres, Tomas1 aHernendez, Vicente1 aMedina, Ignacio1 aTerraga, Joaquin1 aDopazo, Joaquin  uhttp://ieeexplore.ieee.org.sire.ub.edu/xpl/articleDetails.jsp?reload=true&arnumber=617588802712nas a2200325   4500008004100000022001400041245015600055210006900211260001300280300001000293490000700303520157800310653002801888653002201916653004201938653001301980653003401993653001302027653003602040653001302076653002802089100002002117700002402137700001702161700002402178700002002202700002602222700002002248856011802268       2012                        eng d  a1362-496200aVARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.0 aVARIANT Command Line Web service and Web interface for fast and   c2012 Jul  aW54-80 v403 a<p>The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.</p>10aDatabases, Nucleic Acid10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aInternet10aMolecular Sequence Annotation10amutation10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aDe Maria, Alejandro1 aBleda, Marta1 aSalavert, Francisco1 aAlonso, Roberto1 aGonzalez, Cristina, Y1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/variant-command-line-web-service-and-web-interface-fast-and-accurate-functional02869nas a2200493   4500008004100000022001400041245007000055210006800125260001600193300001100209490000600220520139500226653001801621653002701639653002101666653004101687653002001728653002401748653000901772653001101781653001801792653004201810653001101852653003701863653001301900653003801913653002701951653001301978100001701991700001902008700001802027700002502045700002102070700002002091700001902111700002602130700002302156700001802179700001602197700002402213700002002237700002002257856009802277       2012                        eng d  a1559-230800aWhole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.0 aWholegenome bisulfite DNA sequencing of a DNMT3B mutant patient  c2012 Jun 01  a542-500 v73 a<p>The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.</p>10aB-Lymphocytes10aCell Line, Transformed10aChild, Preschool10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methylation10aEpigenesis, Genetic10aFace10aFemale10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aImmunologic Deficiency Syndromes10amutation10aPrimary Immunodeficiency Diseases10aSequence Analysis, DNA10aSulfites1 aHeyn, Holger1 aVidal, Enrique1 aSayols, Sergi1 aSanchez-Mut, Jose, V1 aMoran, Sebastian1 aMedina, Ignacio1 aSandoval, Juan1 aSimó-Riudalbas, Laia1 aSzczesna, Karolina1 aHuertas, Dori1 aGatto, Sole1 aMatarazzo, Maria, R1 aDopazo, Joaquin1 aEsteller, Manel  uhttp://clinbioinfosspa.es/content/whole-genome-bisulfite-dna-sequencing-dnmt3b-mutant-patient02092nas a2200241   4500008004100000245015300041210006900194260000900263300001100272490000600283520122100289100002001510700002301530700002101553700002401574700002101598700001801619700002201637700002001659700002301679700002401702856012401726       2011                        eng d00aAnalysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells.0 aAnalysis of normaltumour tissue interaction in tumours predictio  c2011  ae164920 v63 a<p>Statistical modelling, in combination with genome-wide expression profiling techniques, has demonstrated that the molecular state of the tumour is sufficient to infer its pathological state. These studies have been extremely important in diagnostics and have contributed to improving our understanding of tumour biology. However, their importance in in-depth understanding of cancer patho-physiology may be limited since they do not explicitly take into consideration the fundamental role of the tissue microenvironment in specifying tumour physiology. Because of the importance of normal cells in shaping the tissue microenvironment we formulate the hypothesis that molecular components of the profile of normal epithelial cells adjacent the tumour are predictive of tumour physiology. We addressed this hypothesis by developing statistical models that link gene expression profiles representing the molecular state of adjacent normal epithelial cells to tumour features in prostate cancer. Furthermore, network analysis showed that predictive genes are linked to the activity of important secreted factors, which have the potential to influence tumor biology, such as IL1, IGF1, PDGF BB, AGT, and TGF&beta;.</p>1 aTrevino, Victor1 aTadesse, Mahlet, G1 aVannucci, Marina1 aAl-Shahrour, Fatima1 aAntczak, Philipp1 aDurant, Sarah1 aBikfalvi, Andreas1 aDopazo, Joaquin1 aCampbell, Moray, J1 aFalciani, Francesco  uhttp://clinbioinfosspa.es/content/analysis-normal-tumour-tissue-interaction-tumours-prediction-prostate-cancer-features02550nas a2200145   4500008004100000245013600041210006900177260000900246300001100255490000600266520201400272100001902286700002002305856007902325       2011                        eng d00aAssessing the biological significance of gene expression signatures and co-expression modules by studying their network properties.0 aAssessing the biological significance of gene expression signatu  c2011  ae174740 v63 a<p>Microarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role).We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference.Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional contexts.</p>1 aMinguez, Pablo1 aDopazo, Joaquin  uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.001747402499nas a2200277   4500008004100000022001400041245005900055210005600114260001300170300001200183490000700195520165100202653001501853653002801868653003001896653003101926653001101957653002001968653004401988100002002032700003002052700002002082700002002102700001602122856008302138       2011                        eng d  a1549-546900aDifferential expression in RNA-seq: a matter of depth.0 aDifferential expression in RNAseq a matter of depth  c2011 Dec  a2213-230 v213 a<p>Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.</p>10aAlgorithms10aExpressed Sequence Tags10aGene Expression Profiling10aGene Expression Regulation10aHumans10aModels, Genetic10aOligonucleotide Array Sequence Analysis1 aTarazona, Sonia1 aGarcía-Alcalde, Fernando1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/differential-expression-rna-seq-matter-depth02873nas a2200301   4500008004100000245015000041210006900191260001600260300001200276490000700288520183800295100001902133700002202152700002502174700002102199700002002220700002002240700001702260700002102277700002202298700002502320700002102345700002002366700001802386700002102404700002402425856012202449       2011                        eng d00aDifferential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.0 aDifferential Lipid Partitioning Between Adipocytes and Tissue Ma  c2011 Jan 24  a797-8090 v603 a<p>OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.</p>1 aPrieur, Xavier1 aMok, Crystal, Y L1 aVelagapudi, Vidya, R1 aNúñez, Vanessa1 aFuentes, Lucía1 aMontaner, David1 aIshikawa, Ko1 aCamacho, Alberto1 aBarbarroja, Nuria1 aO’Rahilly, Stephen1 aSethi, Jaswinder1 aDopazo, Joaquin1 aOresic, Matej1 aRicote, Mercedes1 aVidal-Puig, Antonio  uhttp://clinbioinfosspa.es/content/differential-lipid-partitioning-between-adipocytes-and-tissue-macrophages-modulates03515nas a2200493   4500008004100000022001400041245012700055210006900182260001600251300000700267490000600274520197600280653001202256653002302268653001802291653001602309653002002325653001102345653003102356653002902387653002302416653002802439653000902467653001202476653002402488653002002512653001502532653002402547653002702571653003602598100001802634700003002652700002302682700002902705700002102734700002002755700001902775700001602794700001602810700002002826700002402846700002302870856012802893       2011                        eng d  a1755-879400aEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.0 aEarly peroxisome proliferatoractivated receptor gamma regulated   c2011 Dec 30  a860 v43 a<p><b>BACKGROUND: </b>The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion</p><p><b>RESULTS: </b>Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.</p><p><b>CONCLUSIONS: </b>Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.</p>10aAnimals10aCell Proliferation10aCell Survival10aCholesterol10aDown-Regulation10aFemale10aGene Expression Regulation10aGene Knockout Techniques10aInsulin Resistance10aInsulin-Secreting Cells10aMice10aobesity10aOxidation-Reduction10aPhosphorylation10aPPAR gamma10aSignal Transduction10aTranscription, Genetic10aTransforming Growth Factor beta1 aVivas, Yurena1 aMartinez-Garcia, Cristina1 aIzquierdo, Adriana1 aGarcia-Garcia, Francisco1 aCallejas, Sergio1 aVelasco, Ismael1 aCampbell, Mark1 aRos, Manuel1 aDopazo, Ana1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aMedina-Gomez, Gema  uhttp://clinbioinfosspa.es/content/early-peroxisome-proliferator-activated-receptor-gamma-regulated-genes-involved-expansion03501nas a2200469   4500008004100000022001400041245011200055210006900167260001300236300001200249490000800261520192600269653001602195653002202211653002802233653002002261653001702281653002102298653003002319653003802349653002202387653001002409653001302419653004402432653003502476653002802511653003102539653005202570653001902622653002402641653002602665653002702691100002902718700002202747700002902769700001802798700002002816700001902836700002302855700002202878856013102900       2011                        eng d  a1532-254800aEarly transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.0 aEarly transcriptional defense responses in Arabidopsis cell susp  c2011 Jul  a1439-560 v1563 a<p>The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2',7'-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.</p>10aArabidopsis10aBlotting, Western10aCell Culture Techniques10aCells, Cultured10aChloroplasts10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Plant10aHydrogen Peroxide10aLight10amutation10aOligonucleotide Array Sequence Analysis10aPhotosystem II Protein Complex10aPlant Growth Regulators10aReproducibility of Results10aReverse Transcriptase Polymerase Chain Reaction10aRNA, Messenger10aSignal Transduction10aStress, Physiological10aTranscription, Genetic1 aGonzález-Pérez, Sergio1 aGutiérrez, Jorge1 aGarcia-Garcia, Francisco1 aOsuna, Daniel1 aDopazo, Joaquin1 aLorenzo, Oscar1 aRevuelta, José, L1 aArellano, Juan, B  uhttp://clinbioinfosspa.es/content/early-transcriptional-defense-responses-arabidopsis-cell-suspension-culture-under-high-light02371nas a2200289   4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520143700274653001201711653002301723653002501746653002101771653002001792653001101812653001101823653000901834653002201843100002401865700002001889700002301909700002001932856012901952       2011                        eng d  a1477-405400aEvidence for short-time divergence and long-time conservation of tissue-specific expression after gene duplication.0 aEvidence for shorttime divergence and longtime conservation of t  c2011 Sep  a442-80 v123 a<p>Gene duplication is one of the main mechanisms by which genomes can acquire novel functions. It has been proposed that the retention of gene duplicates can be associated to processes of tissue expression divergence. These models predict that acquisition of divergent expression patterns should be acquired shortly after the duplication, and that larger divergence in tissue expression would be expected for paralogs, as compared to orthologs of a similar age. Many studies have shown that gene duplicates tend to have divergent expression patterns and that gene family expansions are associated with high levels of tissue specificity. However, the timeframe in which these processes occur have rarely been investigated in detail, particularly in vertebrates, and most analyses do not include direct comparisons of orthologs as a baseline for the expected levels of tissue specificity in absence of duplications. To assess the specific contribution of duplications to expression divergence, we combine here phylogenetic analyses and expression data from human and mouse. In particular, we study differences in spatial expression among human-mouse paralogs, specifically duplicated after the radiation of mammals, and compare them to pairs of orthologs in the same species. Our results show that gene duplication leads to increased levels of tissue specificity and that this tends to occur promptly after the duplication event.</p>10aAnimals10aConserved Sequence10aEvolution, Molecular10aGene Duplication10agene expression10aGenome10aHumans10aMice10aOrgan Specificity1 aHuerta-Cepas, Jaime1 aDopazo, Joaquin1 aHuynen, Martijn, A1 aGabaldón, Toni  uhttp://clinbioinfosspa.es/content/evidence-short-time-divergence-and-long-time-conservation-tissue-specific-expression-after01789nas a2200193   4500008004100000245015100041210006900192260001300261300001300274490000600287520104500293100002001338700001801358700002801376700002001404700002301424700002301447856012501470       2011                        eng d00aAn evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins.0 aevolutionary tradeoff between protein turnover rate and protein   c2011 Jun  ae10020900 v73 a<p>We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ’gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins.</p>1 aDe Baets, Greet1 aReumers, Joke1 aBlanco, Javier, Delgado1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic  uhttp://clinbioinfosspa.es/content/evolutionary-trade-between-protein-turnover-rate-and-protein-aggregation-favors-higher00689nas a2200193   4500008004100000022001400041245010000055210006900155260000900224300000800233490000700241520001400248100002100262700002600283700001600309700002000325700002100345856012900366       2011                        eng d  a1471-222900aFortunella margarita Transcriptional Reprogramming Triggered by Xanthomonas citri subsp. citri.0 aFortunella margarita Transcriptional Reprogramming Triggered by   c2011  a1590 v113 aABSTRACT:1 aKhalaf, Abeer, A1 aGmitter, Frederick, G1 aConesa, Ana1 aDopazo, Joaquin1 aMoore, Gloria, A  uhttp://clinbioinfosspa.es/content/fortunella-margarita-transcriptional-reprogramming-triggered-xanthomonas-citri-subsp-citri03586nas a2200649   4500008004100000022001400041245019000055210006900245260001600314300001200330490000700342520147500349653001801824653002201842653001201864653004901876653002501925653001401950653001701964653002101981653002502002653002002027653001902047653003002066653002902096653001102125653000902136653001802145653002802163653002802191653005202219653002902271653002402300653003002324653004802354653001802402100001402420700001802434700003002452700001602482700002002498700002002518700001702538700002402555700001902579700001902598700002802617700002002645700001902665700002802684700001802712700002202730700002002752700002002772700001902792856012502811       2011                        eng d  a1460-208300aLarge-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.0 aLargescale transcriptional profiling and functional assays revea  c2011 Dec 15  a4932-460 v203 a<p>Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.</p>10aAcute Disease10aAnemia, Hemolytic10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aCell Differentiation10aCell Line10aCell Lineage10aCluster Analysis10aEmbryonic Stem Cells10aErythroid Cells10aFlow Cytometry10aGene Expression Profiling10aHematopoietic Stem Cells10aHumans10aMice10aMyeloid Cells10aParacrine Communication10aProto-Oncogene Proteins10aReverse Transcriptase Polymerase Chain Reaction10arho GTP-Binding Proteins10aSignal Transduction10aStem Cell Transplantation10aT-Cell Acute Lymphocytic Leukemia Protein 110aTranscriptome1 aYung, Sun1 aLedran, Maria1 aMoreno-Gimeno, Inmaculada1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin1 aDimmick, Ian1 aSlater, Nicholas, J1 aMarenah, Lamin1 aReal, Pedro, J1 aParaskevopoulou, Iliana1 aBisbal, Viviana1 aBurks, Deborah1 aSantibanez-Koref, Mauro1 aMoreno, Ruben1 aMountford, Joanne1 aMenendez, Pablo1 aArmstrong, Lyle1 aLako, Majlinda  uhttp://clinbioinfosspa.es/content/large-scale-transcriptional-profiling-and-functional-assays-reveal-important-roles-rho02919nas a2200433   4500008004100000022001400041245013300055210006900188260000900257300001100266490000600277520154700283653001201830653002801842653001001870653002201880653001101902653002301913653001101936653001201947653001301959653001301972653002301985653004402008653003002052653003102082653002502113653001802138100003302156700001902189700002202208700002002230700002002250700002002270700002002290700002002310700002502330856013002355       2011                        eng d  a1932-620300aMutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.0 aMutation screening of multiple genes in Spanish patients with au  c2011  ae278940 v63 a<p>Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.</p>10aAlleles10aDNA Mutational Analysis10aExons10aGenetic Variation10aGenome10aHispanic or Latino10aHumans10aIntrons10aLanguage10amutation10aMutation, Missense10aOligonucleotide Array Sequence Analysis10aPolymerase Chain Reaction10aReproducibility of Results10aRetinitis pigmentosa10aUnited States1 adel Pozo, María, González-1 aBorrego, Salud1 aBarragán, Isabel1 aPieras, Juan, I1 aSantoyo, Javier1 aMatamala, Nerea1 aNaranjo, Belén1 aDopazo, Joaquin1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/mutation-screening-multiple-genes-spanish-patients-autosomal-recessive-retinitis-pigmentosa02481nas a2200277   4500008004100000022001400041245007400055210006900129260000900198300001100207490000600218520162800224653002201852653002301874653001301897653001301910653003401923653002801957100002301985700002402008700001602032700002002048700001902068700001902087856009702106       2011                        eng d  a1932-620300amyKaryoView: a light-weight client for visualization of genomic data.0 amyKaryoView a lightweight client for visualization of genomic da  c2011  ae263450 v63 a<p>The Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView's ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com.</p>10aComputer Graphics10aDatabases, Genetic10aGenomics10aInternet10aMolecular Sequence Annotation10aUser-Computer Interface1 aJimenez, Rafael, C1 aSalazar, Gustavo, A1 aGel, Bernat1 aDopazo, Joaquin1 aMulder, Nicola1 aCorpas, Manuel  uhttp://clinbioinfosspa.es/content/mykaryoview-light-weight-client-visualization-genomic-data02573nas a2200301   4500008004100000022001400041245006900055210006600124260001300190300001300203490000600216520167900222653001201901653002301913653001501936653001901951653003401970653001302004653001202017653001402029653002302043653002702066100002102093700002102114700002002135700002002155856009602175       2011                        eng d  a1553-735800aNatural selection on functional modules, a genome-wide analysis.0 aNatural selection on functional modules a genomewide analysis  c2011 Mar  ae10010930 v73 a<p>Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.</p>10aAnimals10aDatabases, Genetic10aDrosophila10aGenome, Insect10aGenome-Wide Association Study10aGenomics10aMammals10aPhylogeny10aSelection, Genetic10aSequence Analysis, DNA1 aSerra, François1 aArbiza, Leonardo1 aDopazo, Joaquin1 aDopazo, Hernán  uhttp://clinbioinfosspa.es/content/natural-selection-functional-modules-genome-wide-analysis02020nas a2200349   4500008004100000022001400041245011700055210006900172260001300241300001100254490000700265520090400272653002501176653001301201653001301214653001401227653002301241653001301264100002101277700002101298700002301319700002001342700002101362700001701383700002401400700003301424700002401457700002001481700002001501700002001521856012901541       2011                        eng d  a1362-496200aPhylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.0 aPhylemon 20 a suite of webtools for molecular evolution phylogen  c2011 Jul  aW470-40 v393 a<p>Phylemon 2.0 is a new release of the suite of web tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing. It has been designed as a response to the increasing demand of molecular sequence analyses for experts and non-expert users. Phylemon 2.0 has several unique features that differentiates it from other similar web resources: (i) it offers an integrated environment that enables evolutionary analyses, format conversion, file storage and edition of results; (ii) it suggests further analyses, thereby guiding the users through the web server; and (iii) it allows users to design and save phylogenetic pipelines to be used over multiple genes (phylogenomics). Altogether, Phylemon 2.0 integrates a suite of 30 tools covering sequence alignment reconstruction and trimming; tree reconstruction, visualization and manipulation; and evolutionary hypotheses testing.</p>10aEvolution, Molecular10aGenomics10aInternet10aPhylogeny10aSequence Alignment10aSoftware1 aSánchez, Rubén1 aSerra, François1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aPulido, Luis1 aDe Maria, Alejandro1 aCapella-Gutíerrez, Salvador1 aHuerta-Cepas, Jaime1 aGabaldón, Toni1 aDopazo, Joaquin1 aDopazo, Hernán  uhttp://clinbioinfosspa.es/content/phylemon-20-suite-web-tools-molecular-evolution-phylogenetics-phylogenomics-and-hypotheses02773nas a2200385   4500008004100000245011100041210006900152260001300221300001000234490000700244520152200251100002301773700002601796700001901822700002401841700002701865700002901892700002001921700002001941700002801961700001901989700002302008700002402031700002002055700001602075700002302091700001902114700002002133700002002153700002002173700002002193700002502213700002302238856012602261       2010                        eng d00aChanges in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.0 aChanges in the pattern of DNA methylation associate with twin di  c2010 Feb  a170-90 v203 a<p>Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.</p>1 aJavierre, Biola, M1 aFernandez, Agustin, F1 aRichter, Julia1 aAl-Shahrour, Fatima1 aMartin-Subero, Ignacio1 aRodriguez-Ubreva, Javier1 aBerdasco, Maria1 aFraga, Mario, F1 aO’Hanlon, Terrance, P1 aRider, Lisa, G1 aJacinto, Filipe, V1 aLopez-Longo, Javier1 aDopazo, Joaquin1 aForn, Marta1 aPeinado, Miguel, A1 aCarreño, Luis1 aSawalha, Amr, H1 aHarley, John, B1 aSiebert, Reiner1 aEsteller, Manel1 aMiller, Frederick, W1 aBallestar, Esteban  uhttp://clinbioinfosspa.es/content/changes-pattern-dna-methylation-associate-twin-discordance-systemic-lupus-erythematosus03406nas a2200529   4500008004100000022001400041245007000055210006900125260000900194300000800203490000700211520186600218653000902084653002102093653001602114653002002130653002402150653001102174653003002185653001502215653001302230653001102243653001802254653001602272653001302288653002102301653004402322653002102366653003302387100002302420700002502443700001902468700001902487700002002506700002202526700002002548700002602568700002002594700002002614700002202634700002602656700001902682700002002701700002802721700002702749856010002776       2010                        eng d  a1465-542X00aDNA methylation epigenotypes in breast cancer molecular subtypes.0 aDNA methylation epigenotypes in breast cancer molecular subtypes  c2010  aR770 v123 a<p><b>INTRODUCTION: </b>Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.</p><p><b>METHODS: </b>Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.</p><p><b>RESULTS: </b>The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.</p><p><b>CONCLUSIONS: </b>Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.</p>10aAged10aBreast Neoplasms10aCpG Islands10aDNA Methylation10aEpigenesis, Genetic10aFemale10aGene Expression Profiling10aGenes, p5310aGenotype10aHumans10aKi-67 Antigen10aMiddle Aged10amutation10aNeoplasm Grading10aOligonucleotide Array Sequence Analysis10aReceptor, ErbB-210aTumor Suppressor Protein p531 aBediaga, Naiara, G1 aAcha-Sagredo, Amelia1 aGuerra, Isabel1 aViguri, Amparo1 aAlbaina, Carmen1 aDiaz, Irune, Ruiz1 aRezola, Ricardo1 aAlberdi, Maria, Jesus1 aDopazo, Joaquin1 aMontaner, David1 aRenobales, Mertxe1 aFernandez, Agustin, F1 aField, John, K1 aFraga, Mario, F1 aLiloglou, Triantafillos1 ade Pancorbo, Marian, M  uhttp://clinbioinfosspa.es/content/dna-methylation-epigenotypes-breast-cancer-molecular-subtypes02509nas a2200217   4500008004100000022001400041245005200055210005000107260001600157300000700173490000700180520188600187653002602073653002302099653001402122653001302136100002402149700002002173700002002193856007802213       2010                        eng d  a1471-210500aETE: a python Environment for Tree Exploration.0 aETE a python Environment for Tree Exploration  c2010 Jan 13  a240 v113 a<p><b>BACKGROUND: </b>Many bioinformatics analyses, ranging from gene clustering to phylogenetics, produce hierarchical trees as their main result. These are used to represent the relationships among different biological entities, thus facilitating their analysis and interpretation. A number of standalone programs are available that focus on tree visualization or that perform specific analyses on them. However, such applications are rarely suitable for large-scale surveys, in which a higher level of automation is required. Currently, many genome-wide analyses rely on tree-like data representation and hence there is a growing need for scalable tools to handle tree structures at large scale.</p><p><b>RESULTS: </b>Here we present the Environment for Tree Exploration (ETE), a python programming toolkit that assists in the automated manipulation, analysis and visualization of hierarchical trees. ETE libraries provide a broad set of tree handling options as well as specific methods to analyze phylogenetic and clustering trees. Among other features, ETE allows for the independent analysis of tree partitions, has support for the extended newick format, provides an integrated node annotation system and permits to link trees to external data such as multiple sequence alignments or numerical arrays. In addition, ETE implements a number of built-in analytical tools, including phylogeny-based orthology prediction and cluster validation techniques. Finally, ETE's programmable tree drawing engine can be used to automate the graphical rendering of trees with customized node-specific visualizations.</p><p><b>CONCLUSIONS: </b>ETE provides a complete set of methods to manipulate tree data structures that extends current functionality in other bioinformatic toolkits of a more general purpose. ETE is free software and can be downloaded from http://ete.cgenomics.org.</p>10aComputational Biology10aDatabases, Genetic10aPhylogeny10aSoftware1 aHuerta-Cepas, Jaime1 aDopazo, Joaquin1 aGabaldón, Toni  uhttp://clinbioinfosspa.es/content/ete-python-environment-tree-exploration03755nas a2200625   4500008004100000022001400041245009800055210006900153260001600222300001100238490000600249520178700255653001002042653004902052653001102101653002102112653004902133653002502182653002902207653002402236653002802260653001102288653001902299653003802318653003402356653001302390653002302403653001102426653001502437653001102452653003602463653003702499653002902536653003802565653002002603653002002623653002002643653001702663100002102680700002002701700002402721700002702745700002102772700002202793700002202815700002502837700001702862700002002879700002102899700001902920700001902939700002102958700002602979856012403005       2010                        eng d  a1932-620300aExploring the link between germline and somatic genetic alterations in breast carcinogenesis.0 aExploring the link between germline and somatic genetic alterati  c2010 Nov 22  ae140780 v53 a<p>Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.</p>10aAdult10aBone Morphogenetic Protein Receptors, Type I10aBreast10aBreast Neoplasms10aCalcium-Calmodulin-Dependent Protein Kinases10aCase-Control Studies10aCyclin-Dependent Kinases10aDisease Progression10aEstrogen Receptor alpha10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGerm-Line Mutation10aHumans10aOdds Ratio10aPoland10aPolymorphism, Single Nucleotide10aProtein Serine-Threonine Kinases10aProtein-Tyrosine Kinases10aReceptor Protein-Tyrosine Kinases10aReceptor, EphA310aReceptor, EphA710aReceptor, EphB110aRisk Factors1 aBonifaci, Núria1 aGórski, Bohdan1 aMasojć, Bartlomiej1 aWokołorczyk, Dominika1 aJakubowska, Anna1 aDębniak, Tadeusz1 aBerenguer, Antoni1 aMusach, Jordi, Serra1 aBrunet, Joan1 aDopazo, Joaquin1 aNarod, Steven, A1 aLubiński, Jan1 aLázaro, Conxi1 aCybulski, Cezary1 aPujana, Miguel, Angel  uhttp://clinbioinfosspa.es/content/exploring-link-between-germline-and-somatic-genetic-alterations-breast-carcinogenesis02599nas a2200229   4500008004100000245010300041210006900144260001500213300001200228490000800240520175600248100002902004700003802033700002802071700002902099700001802128700002002146700002002166700002302186700003002209856013002239       2010                        eng d00aFM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.0 aFM19G11 a new hypoxiainducible factor HIF modulator affects stem  c2010 Jan 8  a1333-420 v2853 a<p>The biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.</p>1 aMoreno-Manzano, Victoria1 aRodríguez-Jiménez, Francisco, J1 aAceña-Bonilla, Jose, L1 aFustero-Lardíes, Santos1 aErceg, Slaven1 aDopazo, Joaquin1 aMontaner, David1 aStojkovic, Miodrag1 aSánchez-Puelles, Jose, M  uhttp://clinbioinfosspa.es/content/fm19g11-new-hypoxia-inducible-factor-hif-modulator-affects-stem-cell-differentiation-status01714nas a2200229   4500008004100000022001400041245009600055210006900151260001300220300001000233490000600243520095200249653003101201653002901232653001301261653002001274653001301294653002001307100001901327700002001346856011801366       2010                        eng d  a1744-838700aFunctional genomics and networks: new approaches in the extraction of complex gene modules.0 aFunctional genomics and networks new approaches in the extractio  c2010 Feb  a55-630 v73 a<p>The engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.</p>10aGene Expression Regulation10aGene Regulatory Networks10aGenomics10aProtein Binding10aProteins10aSystems biology1 aMinguez, Pablo1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/functional-genomics-and-networks-new-approaches-extraction-complex-gene-modules02384nas a2200301   4500008004100000022001400041245010100055210006900156260001600225300001100241490000600252520140600258653001601664653002301680653003001703653001301733653001101746653004401757100001801801700002001819700001801839700002001857700001901877700002401896700002001920700001801940856012401958       2010                        eng d  a1932-620300aFunctional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.0 aFunctional genomics of 5 to 8cell stage human embryos by blastom  c2010 Oct 26  ae136150 v53 a<p>Blastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.</p>10aBlastomeres10aDNA, Complementary10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis1 aGalan, Amparo1 aMontaner, David1 aPóo, Eugenia1 aValbuena, Diana1 aRuiz, Veronica1 aAguilar, Cristóbal1 aDopazo, Joaquin1 aSimon, Carlos  uhttp://clinbioinfosspa.es/content/functional-genomics-5-8-cell-stage-human-embryos-blastomere-single-cell-cdna-analysis03317nas a2200613   4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013102572       2010                        eng d  a1549-491800aHypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.0 aHypoxia promotes efficient differentiation of human embryonic st  c2010 Mar 31  a407-180 v283 a<p>Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5% O(2), more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.</p>10aAngiopoietin-110aAnimals10abiomarkers10aCell Culture Techniques10aCell Differentiation10aCell Hypoxia10aCell Transplantation10aCells, Cultured10aDown-Regulation10aEmbryonic Stem Cells10aEndothelial Cells10aGene Expression Profiling10aGene Expression Regulation10aHumans10aMale10aMyocardial Infarction10aNeovascularization, Physiologic10aOxygen10aPluripotent Stem Cells10aRats10aRats, Nude10aVascular Endothelial Growth Factor A1 aPrado-Lopez, Sonia1 aConesa, Ana1 aArmiñán, Ana1 aMartínez-Losa, Magdalena1 aEscobedo-Lucea, Carmen1 aGandia, Carolina1 aTarazona, Sonia1 aMelguizo, Dario1 aBlesa, David1 aMontaner, David1 aSanz-González, Silvia1 aSepúlveda, Pilar1 aGötz, Stefan1 aO'Connor, José, Enrique1 aMoreno, Ruben1 aDopazo, Joaquin1 aBurks, Deborah, J1 aStojkovic, Miodrag  uhttp://clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium01700nas a2200265   4500008004100000245004500041210004400086260000900130300001300139490000600152520096600158653000801124653001401132100002001146700001601166700002701182700002001209700002001229700002301249700001901272700001901291700002001310700002001330856008401350       2010                        eng d00aInitial genomics of the human nucleolus.0 aInitial genomics of the human nucleolus  c2010  ae10008890 v63 a<p>We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.</p>10aNGS10anucleolus1 aNémeth, Attila1 aConesa, Ana1 aSantoyo-López, Javier1 aMedina, Ignacio1 aMontaner, David1 aPéterfia, Bálint1 aSolovei, Irina1 aCremer, Thomas1 aDopazo, Joaquin1 aLängst, Gernot  uhttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.100088907842nas a2202545   4500008004100000245014500041210006900186260001300255300001100268490000700279520110300286100001601389700002201405700002201427700002101449700001701470700002301487700001801510700001801528700002601546700001901572700002501591700002201616700002301638700002301661700001801684700001901702700001701721700001201738700002201750700002301772700002301795700001401818700002401832700002001856700001701876700001601893700001701909700002001926700002201946700001701968700001701985700001502002700001602017700001502033700002402048700002102072700001802093700002702111700001802138700002002156700002002176700001902196700001802215700001602233700001702249700001502266700002002281700002102301700001802322700001402340700002402354700002002378700002202398700002002420700002702440700001102467700001402478700001302492700001802505700001702523700002602540700001302566700001302579700002302592700001902615700002202634700002202656700001802678700001902696700002102715700001502736700002102751700001602772700001602788700001702804700002702821700002302848700002102871700001702892700002702909700002002936700001702956700001502973700001402988700002203002700001703024700001903041700001703060700001703077700001503094700002203109700001603131700002703147700002003174700002403194700002003218700002603238700001703264700001503281700001603296700001403312700001703326700002603343700001603369700002203385700001703407700001503424700002103439700003003460700002103490700001903511700001603530700002603546700001203572700002303584700001403607700002303621700002103644700001803665700002003683700002403703700001503727700002403742700002103766700002003787700002103807700001903828700001703847700001103864700001703875700001803892700001303910700001703923700001303940700001403953700001703967700001303984700001903997700003204016700002004048700001904068700001904087700002404106700002004130700002104150700002404171700002104195700002404216700001804240700001904258700001704277700002004294700001704314700002104331700001804352700001704370700001204387700002504399700001904424700002404443700002604467700002504493700001504518700002004533700001704553700001904570700002304589700001604612700002104628700001904649700002004668700001704688700001604705700001504721700001804736700001704754700002204771700001804793700002004811700002504831700002304856700001804879700001504897700001704912700001404929700002204943700002104965700001904986700001605005700001905021700001505040700001205055700001405067700001505081700001705096700001405113700001505127700001505142700001705157700001605174700001605190700002605206856006405232       2010                        eng d00aThe MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.0 aMicroArray Quality Control MAQCII study of common practices for   c2010 Aug  a827-380 v283 a<p>Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, &gt;30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.</p>1 aShi, Leming1 aCampbell, Gregory1 aJones, Wendell, D1 aCampagne, Fabien1 aWen, Zhining1 aWalker, Stephen, J1 aSu, Zhenqiang1 aChu, Tzu-Ming1 aGoodsaid, Federico, M1 aPusztai, Lajos1 aShaughnessy, John, D1 aOberthuer, André1 aThomas, Russell, S1 aPaules, Richard, S1 aFielden, Mark1 aBarlogie, Bart1 aChen, Weijie1 aDu, Pan1 aFischer, Matthias1 aFurlanello, Cesare1 aGallas, Brandon, D1 aGe, Xijin1 aMegherbi, Dalila, B1 aSymmans, Fraser1 aWang, May, D1 aZhang, John1 aBitter, Hans1 aBrors, Benedikt1 aBushel, Pierre, R1 aBylesjo, Max1 aChen, Minjun1 aCheng, Jie1 aCheng, Jing1 aChou, Jeff1 aDavison, Timothy, S1 aDelorenzi, Mauro1 aDeng, Youping1 aDevanarayan, Viswanath1 aDix, David, J1 aDopazo, Joaquin1 aDorff, Kevin, C1 aElloumi, Fathi1 aFan, Jianqing1 aFan, Shicai1 aFan, Xiaohui1 aFang, Hong1 aGonzaludo, Nina1 aHess, Kenneth, R1 aHong, Huixiao1 aHuan, Jun1 aIrizarry, Rafael, A1 aJudson, Richard1 aJuraeva, Dilafruz1 aLababidi, Samir1 aLambert, Christophe, G1 aLi, Li1 aLi, Yanen1 aLi, Zhen1 aLin, Simon, M1 aLiu, Guozhen1 aLobenhofer, Edward, K1 aLuo, Jun1 aLuo, Wen1 aMcCall, Matthew, N1 aNikolsky, Yuri1 aPennello, Gene, A1 aPerkins, Roger, G1 aPhilip, Reena1 aPopovici, Vlad1 aPrice, Nathan, D1 aQian, Feng1 aScherer, Andreas1 aShi, Tieliu1 aShi, Weiwei1 aSung, Jaeyun1 aThierry-Mieg, Danielle1 aThierry-Mieg, Jean1 aThodima, Venkata1 aTrygg, Johan1 aVishnuvajjala, Lakshmi1 aWang, Sue, Jane1 aWu, Jianping1 aWu, Yichao1 aXie, Qian1 aYousef, Waleed, A1 aZhang, Liang1 aZhang, Xuegong1 aZhong, Sheng1 aZhou, Yiming1 aZhu, Sheng1 aArasappan, Dhivya1 aBao, Wenjun1 aLucas, Anne, Bergstrom1 aBerthold, Frank1 aBrennan, Richard, J1 aBuness, Andreas1 aCatalano, Jennifer, G1 aChang, Chang1 aChen, Rong1 aCheng, Yiyu1 aCui, Jian1 aCzika, Wendy1 aDemichelis, Francesca1 aDeng, Xutao1 aDosymbekov, Damir1 aEils, Roland1 aFeng, Yang1 aFostel, Jennifer1 aFulmer-Smentek, Stephanie1 aFuscoe, James, C1 aGatto, Laurent1 aGe, Weigong1 aGoldstein, Darlene, R1 aGuo, Li1 aHalbert, Donald, N1 aHan, Jing1 aHarris, Stephen, C1 aHatzis, Christos1 aHerman, Damir1 aHuang, Jianping1 aJensen, Roderick, V1 aJiang, Rui1 aJohnson, Charles, D1 aJurman, Giuseppe1 aKahlert, Yvonne1 aKhuder, Sadik, A1 aKohl, Matthias1 aLi, Jianying1 aLi, Li1 aLi, Menglong1 aLi, Quan-Zhen1 aLi, Shao1 aLi, Zhiguang1 aLiu, Jie1 aLiu, Ying1 aLiu, Zhichao1 aMeng, Lu1 aMadera, Manuel1 aMartinez-Murillo, Francisco1 aMedina, Ignacio1 aMeehan, Joseph1 aMiclaus, Kelci1 aMoffitt, Richard, A1 aMontaner, David1 aMukherjee, Piali1 aMulligan, George, J1 aNeville, Padraic1 aNikolskaya, Tatiana1 aNing, Baitang1 aPage, Grier, P1 aParker, Joel1 aParry, Mitchell1 aPeng, Xuejun1 aPeterson, Ron, L1 aPhan, John, H1 aQuanz, Brian1 aRen, Yi1 aRiccadonna, Samantha1 aRoter, Alan, H1 aSamuelson, Frank, W1 aSchumacher, Martin, M1 aShambaugh, Joseph, D1 aShi, Qiang1 aShippy, Richard1 aSi, Shengzhu1 aSmalter, Aaron1 aSotiriou, Christos1 aSoukup, Mat1 aStaedtler, Frank1 aSteiner, Guido1 aStokes, Todd, H1 aSun, Qinglan1 aTan, Pei-Yi1 aTang, Rong1 aTezak, Zivana1 aThorn, Brett1 aTsyganova, Marina1 aTurpaz, Yaron1 aVega, Silvia, C1 aVisintainer, Roberto1 avon Frese, Juergen1 aWang, Charles1 aWang, Eric1 aWang, Junwei1 aWang, Wei1 aWestermann, Frank1 aWilley, James, C1 aWoods, Matthew1 aWu, Shujian1 aXiao, Nianqing1 aXu, Joshua1 aXu, Lei1 aYang, Lun1 aZeng, Xiao1 aZhang, Jialu1 aZhang, Li1 aZhang, Min1 aZhao, Chen1 aPuri, Raj, K1 aScherf, Uwe1 aTong, Weida1 aWolfinger, Russell, D  uhttp://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html02107nas a2200241   4500008004100000022001400041245005600055210005500111260001600166300001100182490000600193520139200199653002301591653003001614653002901644653001801673653001301691653001101704653002401715100002001739700002001759856008601779       2010                        eng d  a1932-620300aMultidimensional gene set analysis of genomic data.0 aMultidimensional gene set analysis of genomic data  c2010 Apr 27  ae103480 v53 a<p>Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.</p>10aDatabases, Genetic10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aGenomics10aHumans10aModels, Statistical1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/multidimensional-gene-set-analysis-genomic-data03040nas a2200565   4500008004100000022001400041245009600055210006900151260001300220300001400233490000700247520132400254653002401578653001201602653002501614653002801639653002401667653002501691653001701716653001101733653002101744653002201765653001101787653000901798653002801807653001301835653001301848653003601861653003201897653002501929653001001954653003301964100002201997700001902019700002602038700003302064700002002097700001802117700002302135700002202158700001802180700002402198700001902222700002102241700002202262700002002284700002702304700002502331856011802356       2010                        eng d  a1098-100400aMutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.0 aMutation spectrum of EYS in Spanish patients with autosomal rece  c2010 Nov  aE1772-8000 v313 a<p>Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.</p>10aAmino Acid Sequence10aAnimals10aCase-Control Studies10aDNA Mutational Analysis10aDrosophila Proteins10aEvolution, Molecular10aEye Proteins10aFemale10aGenes, Recessive10aGenetic Variation10aHumans10aMale10aMolecular Sequence Data10amutation10aPedigree10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRetinitis pigmentosa10aSpain10aStructural Homology, Protein1 aBarragán, Isabel1 aBorrego, Salud1 aPieras, Juan, Ignacio1 adel Pozo, María, González-1 aSantoyo, Javier1 aAyuso, Carmen1 aBaiget, Montserrat1 aMillán, José, M1 aMena, Marcela1 aEl-Aziz, Mai, M Abd1 aAudo, Isabelle1 aZeitz, Christina1 aLittink, Karin, W1 aDopazo, Joaquin1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo  uhttp://clinbioinfosspa.es/content/mutation-spectrum-eys-spanish-patients-autosomal-recessive-retinitis-pigmentosa00608nas a2200169   4500008004100000245010100041210006900142300001300211490000600224100002500230700001900255700002700274700001900301700002000320700002000340856007800360       2010                        eng d00aSelection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes0 aSelection upon Genome Architecture Conservation of Functional Ne  ae10009530 v61 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aMarqués-Bonet, Tomás1 aGazave, Elodie1 aNavarro, Arcadi1 aDopazo, Joaquin  uhttp://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.100095301781nas a2200277   4500008004100000022001400041245009200055210006900147260001300216300001200229490000700241520089700248653001501145653003001160653001301190653001301203653001801216653004401234653001301278100002401291700002101315700002001336700002001356700001601376856011101392       2010                        eng d  a1362-496200aSerial Expression Analysis: a web tool for the analysis of serial gene expression data.0 aSerial Expression Analysis a web tool for the analysis of serial  c2010 Jul  aW239-450 v383 a<p>Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.</p>10aAlgorithms10aGene Expression Profiling10aInternet10aKinetics10aLinear Models10aOligonucleotide Array Sequence Analysis10aSoftware1 aNueda, Maria, José1 aCarbonell, José1 aMedina, Ignacio1 aDopazo, Joaquin1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/serial-expression-analysis-web-tool-analysis-serial-gene-expression-data03500nas a2200373   4500008004100000022001400041245014500055210006900200260001300269300001200282490000800294520221900302653001302521653002002534653002102554653003002575653003002605653004202635653002102677653002102698653003302719653001502752653002402767653001302791653004402804653002902848653001402877653001902891100002102910700002502931700002002956700002302976856012702999       2009                        eng d  a1350-087200aExploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.0 aExploring the antimicrobial action of a carbon monoxidereleasing  c2009 Mar  a813-8240 v1553 a<p>We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.</p>10aBiofilms10aCarbon Monoxide10aEscherichia coli10aEscherichia coli Proteins10aGene Expression Profiling10aGene Expression Regulation, Bacterial10aGenes, Bacterial10aGenes, Regulator10aGenetic Complementation Test10aMethionine10aMicrobial Viability10amutation10aOligonucleotide Array Sequence Analysis10aOrganometallic Compounds10aPhenotype10aRNA, Bacterial1 aNobre, Lígia, S1 aAl-Shahrour, Fátima1 aDopazo, Joaquin1 aSaraiva, Lígia, M  uhttp://clinbioinfosspa.es/content/exploring-antimicrobial-action-carbon-monoxide-releasing-compound-through-whole-genome-001768nas a2200205   4500008004100000022001400041245006300055210006200118260001700180300001100197490000700208520113100215653002501346653002601371653001301397653001301410653002401423100002001447856009501467       2009                        eng d  a1873-286000aFormulating and testing hypotheses in functional genomics.0 aFormulating and testing hypotheses in functional genomics  c2009 Feb-Mar  a97-1070 v453 a<p><b>OBJECTIVE: </b>The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the results, relating the available genomic information to the hypotheses that originated the experiment.</p><p><b>METHODS AND RESULTS: </b>Initially, this interpretation has been made on a pre-selection of relevant genes, based on the experimental values, followed by the study of the enrichment in some functional properties. Nevertheless, functional enrichment methods, demonstrated to have a flaw: the first step of gene selection was too stringent given that the cooperation among genes was ignored. The assumption that modules of genes related by relevant biological properties (functionality, co-regulation, chromosomal location, etc.) are the real actors of the cell biology lead to the development of new procedures, inspired in systems biology criteria, generically known as gene-set methods. These methods have been successfully used to analyze transcriptomic and large-scale genotyping experiments as well as to test other different genome-scale hypothesis in other fields such as phylogenomics.</p>10aBiological Evolution10aComputational Biology10aGenomics10aGenotype10aModels, Theoretical1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/formulating-and-testing-hypotheses-functional-genomics-002713nas a2200265   4500008004100000022001400041245005800055210005700113260001600170300000700186490001500193520188200208653002402090653003002114653004402144653001702188100002402205700002502229700002002254700002902274700002002303700002002323700001602343856008802359       2009                        eng d  a1471-210500aFunctional assessment of time course microarray data.0 aFunctional assessment of time course microarray data  c2009 Jun 16  aS90 v10 Suppl 63 a<p><b>MOTIVATION: </b>Time-course microarray experiments study the progress of gene expression along time across one or several experimental conditions. Most developed analysis methods focus on the clustering or the differential expression analysis of genes and do not integrate functional information. The assessment of the functional aspects of time-course transcriptomics data requires the use of approaches that exploit the activation dynamics of the functional categories to where genes are annotated.</p><p><b>METHODS: </b>We present three novel methodologies for the functional assessment of time-course microarray data. i) maSigFun derives from the maSigPro method, a regression-based strategy to model time-dependent expression patterns and identify genes with differences across series. maSigFun fits a regression model for groups of genes labeled by a functional class and selects those categories which have a significant model. ii) PCA-maSigFun fits a PCA model of each functional class-defined expression matrix to extract orthogonal patterns of expression change, which are then assessed for their fit to a time-dependent regression model. iii) ASCA-functional uses the ASCA model to rank genes according to their correlation to principal time expression patterns and assess functional enrichment on a GSA fashion. We used simulated and experimental datasets to study these novel approaches. Results were compared to alternative methodologies.</p><p><b>RESULTS: </b>Synthetic and experimental data showed that the different methods are able to capture different aspects of the relationship between genes, functions and co-expression that are biologically meaningful. The methods should not be considered as competitive but they provide different insights into the molecular and functional dynamic events taking place within the biological system under study.</p>10aComputer Simulation10aGene Expression Profiling10aOligonucleotide Array Sequence Analysis10aTime Factors1 aNueda, Maria, José1 aSebastián, Patricia1 aTarazona, Sonia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/functional-assessment-time-course-microarray-data02417nas a2200469   4500008004100000022001400041245007800055210006900133260001300202300001300215490000700228520094000235653001001175653002101185653003001206653004101236653002601277653001101303653002101314653002201335653004401357653001901401653001801420653002701438100002001465700003001485700002701515700002501542700002101567700002401588700002801612700002601640700002701666700002401693700002201717700002101739700001501760700002001775700002301795700002101818856010801839       2009                        eng d  a1029-240300aFunctional signatures identified in B-cell non-Hodgkin lymphoma profiles.0 aFunctional signatures identified in Bcell nonHodgkin lymphoma pr  c2009 Oct  a1699-7080 v503 a<p>Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.</p>10aAdult10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Leukemic10aGenetic Heterogeneity10aHumans10aLymphoma, B-Cell10aNeoplasm Proteins10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aRNA, Neoplasm10aTranscription, Genetic1 aAggarwal, Mohit1 aSánchez-Beato, Margarita1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aMartínez, Nerea1 aRodríguez, Antonia1 aRuiz-Ballesteros, Elena1 aCamacho, Francisca, I1 aPérez-Rosado, Alberto1 ade la Cueva, Paloma1 aArtiga, María, J1 aPisano, David, G1 aKimby, Eva1 aDopazo, Joaquin1 aVilluendas, Raquel1 aPiris, Miguel, A  uhttp://clinbioinfosspa.es/content/functional-signatures-identified-b-cell-non-hodgkin-lymphoma-profiles03382nas a2200325   4500008004100000022001400041245007200055210006900127260001600196300000800212490000700220520234600227653001502573653002102588653004402609653002602653653002802679653001102707653003002718653001302748653001102761653004402772653003002816653003102846100002002877700001902897700002502916700002002941856009502961       2009                        eng d  a1471-216400aGene set internal coherence in the context of functional profiling.0 aGene set internal coherence in the context of functional profili  c2009 Apr 27  a1970 v103 a<p><b>BACKGROUND: </b>Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.</p><p><b>RESULTS: </b>Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30% of the modules defined by GO terms and 57% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.</p><p><b>CONCLUSION: </b>For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.</p>10aAlgorithms10aBreast Neoplasms10aCarcinoma, Intraductal, Noninfiltrating10aComputational Biology10aDatabases, Nucleic Acid10aFemale10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis10aPapillomavirus Infections10aReproducibility of Results1 aMontaner, David1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-set-internal-coherence-context-functional-profiling01715nas a2200265   4500008004100000245014300041210006900184300001300253490000700266520085600273653001501129653001301144653001101157653002701168653000801195100002001203700002001223700002101243700002601264700002101290700002301311700002401334700002001358856007101378       2009                        eng d00aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies0 aGene setbased analysis of polymorphisms finding pathways or biol  aW340-3440 v373 a<p>Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/</p>10ababelomics10agene set10aGESBAP10apathway-based analysis10aSNP1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fatima1 aDopazo, Joaquin  uhttp://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W34002023nas a2200349   4500008004100000022001400041245014400055210006900199260001300268300001100281490000700292520085700299653002501156653002101181653001101202653001001213653002201223653003401245653001101279653003601290653001301326653002801339100002001367700002001387700002101407700002601428700002101454700002301475700002501498700002001523856013001543       2009                        eng d  a1362-496200aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.0 aGene setbased analysis of polymorphisms finding pathways or biol  c2009 Jul  aW340-40 v373 a<p>Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.</p>10aBiological Phenomena10aBreast Neoplasms10aFemale10aGenes10aGenetic Variation10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gene-set-based-analysis-polymorphisms-finding-pathways-or-biological-processes-associated-001732nas a2200277   4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520083000253653002201083653003701105653002301142653001101165653001301176653003201189653001301221100001901234700001801253700002001271700002501291700002001316856011801336       2009                        eng d  a1362-496200aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.0 aSNOW a webbased tool for the statistical analysis of proteinprot  c2009 Jul  aW109-140 v373 a<p>Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today's biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.</p>10aComputer Graphics10aData Interpretation, Statistical10aDatabases, Protein10aHumans10aInternet10aProtein Interaction Mapping10aSoftware1 aMinguez, Pablo1 aGötz, Stefan1 aMontaner, David1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/snow-web-based-tool-statistical-analysis-protein-protein-interaction-networks-001472nas a2200205   4500008004100000245009600041210006900137300001300206490000700219520083200226653001601058653001201074653000901086100001901095700001301114700002001127700002401147700002001171856007501191       2009                        eng d00aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks0 aSNOW a webbased tool for the statistical analysis of proteinprot  aW109-1140 v373 a<p>Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today’s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.</p>10ainteractome10anetwork10asnow1 aMinguez, Pablo1 aGotz, S.1 aMontaner, David1 aAl-Shahrour, Fatima1 aDopazo, Joaquin  uhttp://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full00463nas a2200121   4500008004100000245008700041210006900128260000700197300001000204490000600214100002000220856010100240       2009                        eng d00aOn the Use of Functional Module Definitions in the Analysis of Genomic Experiments0 aUse of Functional Module Definitions in the Analysis of Genomic   c09  a47-470 v51 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/use-functional-module-definitions-analysis-genomic-experiments01946nas a2200337   4500008004100000022001400041245010400055210006900159260001300228300001100241490000700252520087500259653002101134653002601155653002301181653001101204653003001215653001101245653002701256653002601283653001401309100001601323700001601339700002901355700002501384700001801409700002001427700002001447700002001467856012101487       2008                        eng d  a1089-864600aDirect functional assessment of the composite phenotype through multivariate projection strategies.0 aDirect functional assessment of the composite phenotype through   c2008 Dec  a373-830 v923 a<p>We present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.</p>10aBreast Neoplasms10aComputational Biology10aDatabases, Genetic10aFemale10aGene Expression Profiling10aHumans10aMathematical Computing10aMultivariate Analysis10aPhenotype1 aConesa, Ana1 aBro, Rasmus1 aGarcia-Garcia, Francisco1 aPrats, José, Manuel1 aGötz, Stefan1 aKjeldahl, Karin1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/direct-functional-assessment-composite-phenotype-through-multivariate-projection-001564nas a2200229   4500008004100000022001400041245003200055210003100087260000900118300001100127490000800138520093500146653001201081653002601093653002001119653003001139653001101169653004401180100002001224700002501244856006501269       2008                        eng d  a1064-374500aExpression and microarrays.0 aExpression and microarrays  c2008  a245-550 v4533 a<p>High throughput methodologies have increased by several orders of magnitude the amount of experimental microarray data available. Nevertheless, translating these data into useful biological knowledge remains a challenge. There is a risk of perceiving these methodologies as mere factories that produce never-ending quantities of data if a proper biological interpretation is not provided. Methods of interpreting these data are continuously evolving. Typically, a simple two-step approach has been used, in which genes of interest are first selected based on thresholds for the experimental values, and then enrichment in biologically relevant terms in the annotations of these genes is analyzed in a second step. For various reasons, such methods are quite poor in terms of performance and new procedures inspired by systems biology that directly address sets of functionally related genes are currently under development.</p>10aAnimals10aComputational Biology10agene expression10aGene Expression Profiling10aHumans10aOligonucleotide Array Sequence Analysis1 aDopazo, Joaquin1 aAl-Shahrour, Fátima  uhttp://clinbioinfosspa.es/content/expression-and-microarrays02498nas a2200385   4500008004100000022001400041245007700055210006900132260001600201300001200217490000700229520130100236653002201537653003701559653003001596653001301626653001301639653004401652653001301696100002301709700002001732700002101752700002401773700001901797700001601816700002501832700002801857700001801885700001901903700002901922700001601951700002001967700002001987856010502007       2008                        eng d  a1362-496200aGEPAS, a web-based tool for microarray data analysis and interpretation.0 aGEPAS a webbased tool for microarray data analysis and interpret  c2008 Jul 01  aW308-140 v363 a<p>Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.</p>10aComputer Graphics10aDose-Response Relationship, Drug10aGene Expression Profiling10aInternet10aKinetics10aOligonucleotide Array Sequence Analysis10aSoftware1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aAlloza, Eva1 aAl-Shahrour, Fátima1 aVegas-Azcárate, Susana1 aGoetz, Stefan1 aEscobar, Pablo1 aGarcia-Garcia, Francisco1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/gepas-web-based-tool-microarray-data-analysis-and-interpretation-002717nas a2200385   4500008004100000022001400041245008300055210006900138260001300207300001200220490000700232520153300239653001201772653002601784653002201810653002301832653002801855653001001883653001301893653002701906653003101933653001301964653002701977100001802004700003302022700001802055700002102073700002902094700002402123700002302147700001802170700002002188700001602208856010702224       2008                        eng d  a1362-496200aHigh-throughput functional annotation and data mining with the Blast2GO suite.0 aHighthroughput functional annotation and data mining with the Bl  c2008 Jun  a3420-350 v363 a<p>Functional genomics technologies have been widely adopted in the biological research of both model and non-model species. An efficient functional annotation of DNA or protein sequences is a major requirement for the successful application of these approaches as functional information on gene products is often the key to the interpretation of experimental results. Therefore, there is an increasing need for bioinformatics resources which are able to cope with large amount of sequence data, produce valuable annotation results and are easily accessible to laboratories where functional genomics projects are being undertaken. We present the Blast2GO suite as an integrated and biologist-oriented solution for the high-throughput and automatic functional annotation of DNA or protein sequences based on the Gene Ontology vocabulary. The most outstanding Blast2GO features are: (i) the combination of various annotation strategies and tools controlling type and intensity of annotation, (ii) the numerous graphical features such as the interactive GO-graph visualization for gene-set function profiling or descriptive charts, (iii) the general sequence management features and (iv) high-throughput capabilities. We used the Blast2GO framework to carry out a detailed analysis of annotation behaviour through homology transfer and its impact in functional genomics research. Our aim is to offer biologists useful information to take into account when addressing the task of functionally characterizing their sequence data.</p>10aAnimals10aComputational Biology10aComputer Graphics10aDatabases, Genetic10aExpressed Sequence Tags10aGenes10aGenomics10aSequence Analysis, DNA10aSequence Analysis, Protein10aSoftware10aVocabulary, Controlled1 aGötz, Stefan1 aGarcía-Gómez, Juan, Miguel1 aTerol, Javier1 aWilliams, Tim, D1 aNagaraj, Shivashankar, H1 aNueda, Maria, José1 aRobles, Montserrat1 aTalon, Manuel1 aDopazo, Joaquin1 aConesa, Ana  uhttp://clinbioinfosspa.es/content/high-throughput-functional-annotation-and-data-mining-blast2go-suite03685nas a2200937   4500008004100000022001400041245007800055210006900133260001300202300001100215490000600226520100100232653002601233653003201259653002301291653003801314653001301352653002601365653002401391110002301415700002301438700001901461700001801480700002501498700001801523700001901541700002101560700001601581700001601597700002901613700001701642700001901659700002201678700002501700700003101725700002501756700001601781700001901797700001601816700002001832700002601852700002501878700001901903700001901922700001801941700001901959700001401978700001901992700002002011700002002031700001702051700002002068700002102088700002402109700002102133700002102154700002102175700002202196700001802218700002002236700002302256700002402279700002502303700002002328700002002348700002002368700002002388700002202408700002002430700002302450700001702473700001602490700002702506700001802533700001802551700001902569700002002588700001802608700002302626856009802649       2008                        eng d  a1477-405400aInteroperability with Moby 1.0--it's better than sharing your toothbrush!0 aInteroperability with Moby 10its better than sharing your toothb  c2008 May  a220-310 v93 a<p>The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.</p>10aComputational Biology10aDatabase Management Systems10aDatabases, Factual10aInformation Storage and Retrieval10aInternet10aProgramming Languages10aSystems Integration1 aBioMoby Consortium1 aWilkinson, Mark, D1 aSenger, Martin1 aKawas, Edward1 aBruskiewich, Richard1 aGouzy, Jerome1 aNoirot, Celine1 aBardou, Philippe1 aNg, Ambrose1 aHaase, Dirk1 aSaiz, Enrique, de Andres1 aWang, Dennis1 aGibbons, Frank1 aGordon, Paul, M K1 aSensen, Christoph, W1 aCarrasco, Jose, Manuel Rod1 aFernández, José, M1 aShen, Lixin1 aLinks, Matthew1 aNg, Michael1 aOpushneva, Nina1 aNeerincx, Pieter, B T1 aLeunissen, Jack, A M1 aErnst, Rebecca1 aTwigger, Simon1 aUsadel, Bjorn1 aGood, Benjamin1 aWong, Yan1 aStein, Lincoln1 aCrosby, William1 aKarlsson, Johan1 aRoyo, Romina1 aPárraga, Iván1 aRamírez, Sergio1 aGelpi, Josep, Lluis1 aTrelles, Oswaldo1 aPisano, David, G1 aJimenez, Natalia1 aKerhornou, Arnaud1 aRosset, Roman1 aZamacola, Leire1 aTárraga, Joaquín1 aHuerta-Cepas, Jaime1 aCarazo, Jose, María1 aDopazo, Joaquin1 aGuigó, Roderic1 aNavarro, Arcadi1 aOrozco, Modesto1 aValencia, Alfonso1 aClaros, Gonzalo1 aPérez, Antonio, J1 aAldana, Jose1 aRojano, Mar1 aCruz, Raul, Fernandez-1 aNavas, Ismael1 aSchiltz, Gary1 aFarmer, Andrew1 aGessler, Damian1 aSchoof, Heiko1 aGroscurth, Andreas  uhttp://clinbioinfosspa.es/content/interoperability-moby-10-its-better-sharing-your-toothbrush02956nas a2200409   4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520167500289653002801964653001201992653002302004653002902027653003002056653001102086653001302097653000902110653001402119653001302133653003602146653001302182653000902195653002102204653002602225100001802251700001702269700002002286700002802306700002102334700002002355700002302375700002302398856012502421       2008                        eng d  a1362-496200aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.0 aJoint annotation of coding and noncoding single nucleotide polym  c2008 Jan  aD825-90 v363 a<p>Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.</p>10aAmino Acid Substitution10aAnimals10aDatabases, Genetic10aGenetic Diseases, Inborn10aHSP70 Heat-Shock Proteins10aHumans10aInternet10aMice10aMicroRNAs10amutation10aPolymorphism, Single Nucleotide10aProteins10aRats10aRNA Splice Sites10aTranscription Factors1 aReumers, Joke1 aConde, Lucia1 aMedina, Ignacio1 aMaurer-Stroh, Sebastian1 aVan Durme, Joost1 aDopazo, Joaquin1 aRousseau, Frederic1 aSchymkowitz, Joost  uhttp://clinbioinfosspa.es/content/joint-annotation-coding-and-non-coding-single-nucleotide-polymorphisms-and-mutations-002125nas a2200301   4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520123800230653001801468653002101486653001001507653001301517653002101530653001101551653001401562653001301576653002901589653002301618100002401641700001801665700002001683700002001703856010001723       2008                        eng d  a1362-496200aPhylomeDB: a database for genome-wide collections of gene phylogenies.0 aPhylomeDB a database for genomewide collections of gene phylogen  c2008 Jan  aD491-60 v363 a<p>The complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.</p>10aBase Sequence10aEscherichia coli10aGenes10aGenomics10aHistory, Ancient10aHumans10aPhylogeny10aProteins10aSaccharomyces cerevisiae10aSequence Alignment1 aHuerta-Cepas, Jaime1 aBueno, Anibal1 aDopazo, Joaquin1 aGabaldón, Toni  uhttp://clinbioinfosspa.es/content/phylomedb-database-genome-wide-collections-gene-phylogenies-003449nas a2200877   4500008004100000022001400041245006300055210006200118260001300180300001000193490000700203520101900210653001201229653002301241653002301264653001101287653001501298653002701313653001401340653003601354653002801390653000901418653002501427653002701452110002001479700001801499700001701517700003001534700001701564700002401581700001501605700001801620700002401638700002001662700001701682700001801699700001901717700001601736700002401752700002001776700001901796700002101815700001901836700001601855700001701871700001901888700001801907700001701925700002201942700001701964700001901981700001802000700002302018700001802041700002002059700002002079700001802099700002102117700003402138700002202172700002102194700002302215700002202238700002302260700002002283700002002303700002202323700002202345700002002367700002002387700001802407700002002425700001902445700002002464856008702484       2008                        eng d  a1546-171800aSNP and haplotype mapping for genetic analysis in the rat.0 aSNP and haplotype mapping for genetic analysis in the rat  c2008 May  a560-60 v403 a<p>The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.</p>10aAnimals10aChromosome Mapping10aDatabases, Genetic10aGenome10aHaplotypes10aLinkage Disequilibrium10aPhylogeny10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRats10aRats, Inbred Strains10aRecombination, Genetic1 aSTAR Consortium1 aSaar, Kathrin1 aBeck, Alfred1 aBihoreau, Marie-Thérèse1 aBirney, Ewan1 aBrocklebank, Denise1 aChen, Yuan1 aCuppen, Edwin1 aDemonchy, Stephanie1 aDopazo, Joaquin1 aFlicek, Paul1 aFoglio, Mario1 aFujiyama, Asao1 aGut, Ivo, G1 aGauguier, Dominique1 aGuigó, Roderic1 aGuryev, Victor1 aHeinig, Matthias1 aHummel, Oliver1 aJahn, Niels1 aKlages, Sven1 aKren, Vladimir1 aKube, Michael1 aKuhl, Heiner1 aKuramoto, Takashi1 aKuroki, Yoko1 aLechner, Doris1 aLee, Young-Ae1 aLopez-Bigas, Nuria1 aLathrop, Mark1 aMashimo, Tomoji1 aMedina, Ignacio1 aMott, Richard1 aPatone, Giannino1 aPerrier-Cornet, Jeanne-Antide1 aPlatzer, Matthias1 aPravenec, Michal1 aReinhardt, Richard1 aSakaki, Yoshiyuki1 aSchilhabel, Markus1 aSchulz, Herbert1 aSerikawa, Tadao1 aShikhagaie, Medya1 aTatsumoto, Shouji1 aTaudien, Stefan1 aToyoda, Atsushi1 aVoigt, Birger1 aZelenika, Diana1 aZimdahl, Heike1 aHubner, Norbert  uhttp://clinbioinfosspa.es/content/snp-and-haplotype-mapping-genetic-analysis-rat-003089nas a2200385   4500008004100000022001400041245013400055210006900189260001300258300001200271490000700283520182800290653001502118653001002133653002602143653002302169653002802192653002502220653003802245653002202283653001802305653001102323653001802334653001902352653003602371653001302407653003302420100002202453700002102475700001802496700002002514700002002534700002502554856012402579       2008                        eng d  a1098-100400aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.0 aUse of estimated evolutionary strength at the codon level improv  c2008 Jan  a198-2040 v293 a<p>Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.</p>10aAlgorithms10aCodon10aComputational Biology10aDatabases, Protein10aDNA Mutational Analysis10aEvolution, Molecular10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aIduronic Acid10aPoint Mutation10aPolymorphism, Single Nucleotide10aProteins10aTumor Suppressor Protein p531 aCapriotti, Emidio1 aArbiza, Leonardo1 aCasadio, Rita1 aDopazo, Joaquin1 aDopazo, Hernán1 aMarti-Renom, Marc, A  uhttp://clinbioinfosspa.es/content/use-estimated-evolutionary-strength-codon-level-improves-prediction-disease-related-002296nas a2200421   4500008004100000022001400041245005300055210005100108260001300159300001100172490000700183520104700190653001501237653002401252653002601276653003701302653002301339653001301362653002801375653002501403653001301428653002701441653002301468653003101491653003401522653001301556653003601569100002501605700001901630700002201649700001801671700002101689700001901710700002501729700002001754700001701774856008301791       2007                        eng d  a1362-496200aDBAli tools: mining the protein structure space.0 aDBAli tools mining the protein structure space  c2007 Jul  aW393-70 v353 a<p>The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.</p>10aAlgorithms10aAmino Acid Sequence10aComputational Biology10aData Interpretation, Statistical10aDatabases, Protein10aInternet10aMolecular Sequence Data10aProtein Conformation10aProteins10aPseudomonas aeruginosa10aSequence Alignment10aSequence Analysis, Protein10aSequence Homology, Amino Acid10aSoftware10aStructure-Activity Relationship1 aMarti-Renom, Marc, A1 aPieper, Ursula1 aMadhusudhan, M, S1 aRossi, Andrea1 aEswar, Narayanan1 aDavis, Fred, P1 aAl-Shahrour, Fátima1 aDopazo, Joaquin1 aSali, Andrej  uhttp://clinbioinfosspa.es/content/dbali-tools-mining-protein-structure-space-002985nas a2200421   4500008004100000022001400041245007000055210006800125260001600193300000800209490000600217520169900223653003601922653003001958653004301988653001102031653000902042653002302051653002002074653002402094653002202118653001402140653002402154653003202178653001902210653002402229653002002253100002202273700002402295700002002319700002502339700001602364700001702380700002202397700002002419700002602439856009802465       2007                        eng d  a1471-216400aEvidence for systems-level molecular mechanisms of tumorigenesis.0 aEvidence for systemslevel molecular mechanisms of tumorigenesis  c2007 Jun 20  a1850 v83 a<p><b>BACKGROUND: </b>Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.</p><p><b>RESULTS: </b>Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.</p><p><b>CONCLUSION: </b>Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.</p>10aCell Transformation, Neoplastic10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aModels, Biological10aModels, Genetic10aModels, Statistical10aNeoplasm Proteins10aNeoplasms10aProstatic Neoplasms10aProtein Interaction Mapping10aRNA, Messenger10aSignal Transduction10aSystems biology1 aHernández, Pilar1 aHuerta-Cepas, Jaime1 aMontaner, David1 aAl-Shahrour, Fátima1 aValls, Joan1 aGómez, Laia1 aCapellà, Gabriel1 aDopazo, Joaquin1 aPujana, Miguel, Angel  uhttp://clinbioinfosspa.es/content/evidence-systems-level-molecular-mechanisms-tumorigenesis-002675nas a2200385   4500008004100000022001400041245016600055210006900221260001300290300001000303490000700313520140700320653002201727653001201749653001801761653002601779653003001805653001001835653001301845653001101858653001301869653004401882653002601926653001301952653002401965653002601989100002502015700001902040700002302059700002002082700001602102700002002118700002002138856013102158       2007                        eng d  a1362-496200aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.0 aFatiGO a functional profiling tool for genomic data Integration   c2007 Jul  aW91-60 v353 a<p>The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.</p>10aAmino Acid Motifs10aAnimals10aBinding Sites10aComputational Biology10aGene Expression Profiling10aGenes10aGenomics10aHumans10aInternet10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aTranscription Factors1 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aTárraga, Joaquín1 aMedina, Ignacio1 aAlloza, Eva1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/fatigo-functional-profiling-tool-genomic-data-integration-functional-annotation-regulatory-002514nas a2200337   4500008004100000022001400041245007300055210006900128260001600197300000800213490000600221520148900227653001501716653002301731653002401754653003001778653002301808653002101831653002401852653001301876653002001889653002801909100002501937700002101962700002001983700002402003700001902027700002002046700002002066856009002086       2007                        eng d  a1471-210500aFrom genes to functional classes in the study of biological systems.0 aFrom genes to functional classes in the study of biological syst  c2007 Apr 03  a1140 v83 a<p><b>BACKGROUND: </b>With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.</p><p><b>RESULTS: </b>Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.</p><p><b>CONCLUSION: </b>Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.</p>10aAlgorithms10aChromosome Mapping10aComputer Simulation10aGene Expression Profiling10aModels, Biological10aMultigene Family10aSignal Transduction10aSoftware10aSystems biology10aUser-Computer Interface1 aAl-Shahrour, Fátima1 aArbiza, Leonardo1 aDopazo, Hernán1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/genes-functional-classes-study-biological-systems-001766nas a2200205   4500008004100000022001400041245009400055210006900149260001600218300001000234490000600244520105200250100001701302700002001319700002701339700002301366700002501389700002001414856012601434       2007                        eng d  a0973-206300aFunctional profiling and gene expression analysis of chromosomal copy number alterations.0 aFunctional profiling and gene expression analysis of chromosomal  c2007 Apr 10  a432-50 v13 a<p>Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.</p>1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/functional-profiling-and-gene-expression-analysis-chromosomal-copy-number-alterations-001718nas a2200277   4500008004100000022001400041245009000055210006900145260001600214300001100230490000700241520077800248653002801026653002301054653003001077653003801107653003201145653001301177653002001190653002401210100001901234700002501253700002001278700002001298856012201318       2007                        eng d  a1367-481100aFunctional profiling of microarray experiments using text-mining derived bioentities.0 aFunctional profiling of microarray experiments using textmining   c2007 Nov 15  a3098-90 v233 a<p><b>MOTIVATION: </b>The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.</p>10aArtificial Intelligence10aDatabases, Protein10aGene Expression Profiling10aInformation Storage and Retrieval10aNatural Language Processing10aProteins10aResearch Design10aSystems Integration1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aMontaner, David1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/functional-profiling-microarray-experiments-using-text-mining-derived-bioentities-002054nas a2200385   4500008004100000022001400041245012300055210006900178260001300247300001000260490000700270520079500277653001201072653002101084653002601105653002201131653003001153653001101183653001301194653002001207653003101227653004401258653002601302653001301328653002401341653002801365100001701393700002001410700002701430700002301457700002001480700002501500700002001525856012301545       2007                        eng d  a1362-496200aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.0 aISACGH a webbased environment for the analysis of Array CGH and   c2007 Jul  aW81-50 v353 a<p>We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.</p>10aAnimals10aCluster Analysis10aComputational Biology10aComputer Graphics10aGene Expression Profiling10aHumans10aInternet10aModels, Genetic10aNucleic Acid Hybridization10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aUser-Computer Interface1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aMedina, Ignacio1 aAl-Shahrour, Fátima1 aDopazo, Joaquin  uhttp://clinbioinfosspa.es/content/isacgh-web-based-environment-analysis-array-cgh-and-gene-expression-which-includes-0